CRF receptor antagonists

ABSTRACT

The present invention relates to tricyclic pyrimidines compounds of formula (I) including stereoisomers, prodrugs and pharmaceutically acceptable salts or solvates thereof, 
                         
to processes for their preparation, to pharmaceutical compositions containing them and to their use in the treatment of conditions mediated by corticotropin-releasing factor (CRF).

The present invention relates to tricyclic derivatives, to processes fortheir preparation, to pharmaceutical compositions containing them and totheir use in therapy.

The first corticotropin-releasing factor (CRF) was isolated from ovinehypothalami and identified as a 41-amino acid peptide (Vale et al.,Science 213: 1394-1397, 1981).

CRF has been found to produce profound alterations in endocrine, nervousand immune system function. CRF is believed to be the majorphysiological regulator of the basal and stress-release ofadrenocorticotropic hormone (“ACTH”), Bendorphin, and otherpropiomelanocortin (“POMC”)-derived peptides from the anterior pituitary(Vale et al., Science 213: 1394-1397, 1981).

In addition to its role in stimulating the production of ACTH and POMC,CRF appears to be one of the pivotal central nervous systemneurotransmitters and plays a crucial role in integrating the body'soverall response to stress.

Administration of CRF directly to the brain elicits behavioral,physiological, and endocrine responses identical to those observed foran animal exposed to a stressful environment.

Accordingly, clinical data suggests that CRF receptor antagonists may beuseful in the treatment of the neuropsychiatric disorders manifestinghypersecretion of CRF, and, in particular, may represent novelantidepressant and/or anxiolytic drugs.

The first CRF receptor antagonists were peptides (see, e.g., Rivier etal., U.S. Pat. No. 4,605,642; Rivier et al., Science 224: 889, 1984).While these peptides established that CRF receptor antagonists canattenuate the pharmacological responses to CRF, peptide CRF receptorantagonists suffer from the usual drawbacks of peptide therapeuticsincluding lack of stability and limited oral activity. More recently,small molecule CRF receptor antagonists have been reported.

WO 00/27846 discloses CRF receptor antagonists with the followinggeneral formula (A)

with the proviso that at least one of A, B and C is nitrogen, A, B and Care not all nitrogen and either A-B or B-C is a double bond. A, B and Cmay be nitrogen or carbon.

Due to the physiological significance of CRF, the development ofbiologically-active small molecules having significant CRF receptorbinding activity and which are capable of antagonizing the CRF receptorremains a desirable goal. Such CRF receptor antagonists would be usefulin the treatment of endocrine, psychiatric and neurologic conditions orillnesses, including stress-related disorders in general.

While significant strides have been made toward achieving CRF regulationthrough administration of CRF receptor antagonists, there remains a needin the art for effective small molecule CRF receptor antagonists. Thereis also a need for pharmaceutical compositions containing such CRFreceptor antagonists, as well as methods relating to the use thereof totreat, for example, stress-related disorders. The present inventionfulfills these needs, and provides other related advantages.

In particular the invention relates to novel compounds which are potentand specific antagonists of corticotropin-releasing factor (CRF)receptors.

The present invention provides compounds of formula (I) includingstereoisomers, prodrugs and pharmaceutically acceptable salts orsolvates thereof

wherein

-   -   R is aryl or heteroaryl, wherein each of the above groups R may        be substituted by 1 to 4 substituents indendently selected from        the group consisting of:        -   halogen, C1-C6 alkyl, C1-C6 alkoxy, halo C1-C6 alkyl, C2-C6            alkenyl, C2-C6 alkynyl, halo C1-C6 alkoxy, C1-C6 mono or            dialkylamino, nitro, cyano and a group R₄;    -   R₁ is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo        C1-C6 alkyl, halo C1-C6 alkoxy, NH₂, halogen or cyano;    -   R₂ is hydrogen or C(H)_(n)(R₅)_(q)(CH₂)_(p)ZR₆;    -   R₃ is hydrogen, C2-C6 alkenyl, C2-C6 alkynyl or        [CH(R₅)(CH₂)_(p)]_(m)ZR₆;    -   R₄ is C3-C7 cycloalkyl, which may contain one or more double        bonds; aryl; or a 5-6 membered heterocycle;        -   wherein each of the above groups R₄ may be substituted by            one or more groups selected from: halogen, C1-C6 alkyl,            C1-C6 alkoxy, halo C1-C6 alkyl, C2-C6 alkenyl, C2-C6            alkynyl, halo C1-C6 alkoxy, C1-C6 mon a or dialkylamino,            nitro, and cyano;    -   R₅ is hydrogen, C2-C6 alkenyl, C2-C6 alkynyl or (CH₂)_(p)ZR₆;    -   R₆ is C1-C6 alkyl, which may be substituted by one or more        groups selected from halogen, halo C1-C6 alkyl, C2-C6 alkenyl,        C2-C6 alkynyl, halo C1-C6 alkoxy, C1-C6 alkoxy, C1-C6 mono or        dialkylamino, nitro, cyano and a group R₄;    -   Y and X are independently carbon or nitrogen;    -   m and n are independently 0 or 1;    -   p is 0 or an integer from 1 to 4;    -   q is 1 or 2;    -   Z is a bond, O, NH or S.

Acid addition salts of the free base amino compounds of the presentinvention may be prepared by methods well known in the art, and may beformed from organic and inorganic acids. Suitable organic acids includemaleic, malic, fumaric, benzoic, ascorbic, succinic, methanesulfonic,p-toluensulfonic, acetic, oxalic, propionic, tartaric, salicylic,citric, gluconic, lactic, mandelic, cinnamic, aspartic, stearic,palmitic, glycolic, glutamic, and benzenesulfonic acids. Suitableinorganic acids include hydrochloric, hydrobrornic, sulfuric,phosphoric, and nitric acids. Thus, the term “pharmaceuticallyacceptable salt” of structure (I) is intended to encompass any and allacceptable salt forms.

The solvates may, for example, be hydrates.

References hereinafter to a compound according to the invention includeboth compounds of formula (I) and their pharmaceutically acceptable acidaddition salts together with pharmaceutically acceptable solvates.

In addition, prodrugs are also included within the context of thisinvention. Prodrugs are any covalently bonded carriers that release acompound of structure (I) in vivo when such prodrug is administered to apatient. Prodrugs are generally prepared by modifying functional groupsin a way such that the modification is cleaved, either by routinemanipulation or in vivo, yielding the parent compound. Prodrugs include,for example, compounds of this invention wherein hydroxy, amine orsulfhydryl groups are bonded to any group that, when administered to apatient, cleaves to form the hydroxy, amine or sulfhydryl groups. Thus,representative examples of prodrugs include (but are not limited to)acetate, formate and benzoate derivatives of alcohol, sulfhydryl andamine functional groups of the compounds of structure (I). Further, inthe case of a carboxylic acid (—COOH), esters may be employed, such asmethyl esters, ethyl esters, and the like.

With regard to stereoisomers, the compounds of structure (I) may havechiral centers and may occur as recemates, racemic mixtures and asindividual enantiomers or diastereomers. All such isomeric forms areincluded within the present invention, including mixtures thereof.Furthermore, some of the crystalline forms of the compounds of structure(I) may exist as polymorphs, which are included in the presentinvention.

The term C1-C6 alkyl as used herein as a group or a part of the grouprefers to a straight or branched alkyl group containing from 1 to 6carbon atoms; examples of such groups include methyl, ethyl, propyl,isopropyl, n-butyl, isobutyl, tert butyl, pentyl or hexyl.

The term C3-C7 cycloalkyl group means a non aromatic monocyclichydrocarbon ring of 3 to 7 carbon atom such as, for example,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl; whileunsaturated cycloalkyls include cyclopentenyl and cyclohexenyl, and thelike.

The term halogen refers to a fluorine, chlorine, bromine or iodine atom.

The term halo C1-C6 alkyl means an alkyl group having one to six carbonatoms and wherein at least one hydrogen atom is replaced with halogensuch as for example a trifluoromethyl group and the like.

The term C2-C6 alkenyl defines straight or branched chain hydrocarbonradicals containing one or more double bond and having from 2 to 6carbon atoms such as, for example, ethenyl, 2-propenyl, 3-butenyl,2-butenyl, 2-pentenyl, 3-pentenyl, 3-methyl-2-butenyl or 3-hexenyl andthe like.

The term C1-C6 alkoxy group may be a straight or a branched chain alkoxygroup, for example methoxy, ethoxy, propoxy, prop-2-oxy, butoxy,but-2-oxy or methylprop-2-oxy and the like.

The term halo C1-C6 alkoxy group may be a C1-C6 alkoxy group as definedbefore substituted with at least one halogen, preferably fluorine, suchas OCHF₂, or OCF₃.

The term C2-C6 alkynyl defines straight or branched chain hydrocarbonradicals containing one or more triple bond and having from 2 to 6carbon atoms including acetylenyl, propynyl, 1-butynyl, 1-pentynyl,3-methyl-1-butynyl and the like.

The term C1-C6 mono or dialkylamino represents an amino groupindependently substituted with one or two C1-C6 alkyl groups, as definedbefore.

The term aryl means an aromatic carbocyclic moiety such as phenyl,biphenyl or naphthyl.

The term heteroaryl means an aromatic heterocycle ring of 5- to 10members and having at least one heteroatom selected from nitrogen,oxygen and sulfur, and containing at least 1 carbon atom, including bothmono- and bicyclic ring systems.

Representative heteroaryls include (but are not limited to) furyl,benzofuranyl, thiophenyl, benzothiophenyl, pyrrolyl, indolyl,isoindolyl, azaindolyl, pyridyl, quinolinyl, isoquinolinyl, oxazolyl,isooxazolyl, benzoxazolyl, pyrazolyl, imidazolyl, benzimidazolyl,thiazolyl, benzothiazolyl, isothiazolyl, pyridazinyl, pyrimidinyl,pyrazinyl, triazinyl, cinnolinyl, phthalazinyl, and quinazolinyl.

The term heterocycle means a 5 to 7-membered monocyclic, or 7- to14-membered polycyclic, heterocycle ring which is either saturated,unsaturated or aromatic, and which contains from 1 to 4 heteroatomsindependently selected from nitrogen, oxygen and sulfur, and wherein thenitrogen and sulfur heteroatoms may be optionally oxidized, and thenitrogen heteroatom may be optionally quaternized, including bicyclicrings in which any of the above heterocycles are fused to a benzene ringas well as tricyclic (and higher) heterocyclic rings. The heterocyclemay be attached via any heteroatom or carbon atom. Heterocycles includeheteroaryls as defined above. Thus, in addition to the aromaticheteroaryls listed above, heterocycles also include (but are not limitedto) morpholinyl, pyrrolidinonyl, pyrrolidinyl, piperidinyl, hydantoinyl,valerolactamyl, oxiranyl, oxetanyl, tetrahydrofuranyl,tetrahydropyranyl, tetrahydropyridinyl, tetrahydroprimidinyl,tetrahydrothiophenyl, tetrahydrothiopyranyl, tetrahydropyrimidinyl,tetrahydrothiophenyl, tetrahydrothiopyranyl, and the like.

The term 5-6 membered heterocycle means, according to the abovedefinition, a monocyclic heterocyclic ring which is either saturated,unsaturated or aromatic, and which contains from 1 to 4 heteroatomsindependently selected from nitrogen, oxygen and sulfur, and wherein thenitrogen and sulfur heteroatoms may be optionally oxidized, and thenitrogen heteroatom may be optionally quaternized. The heterocycle maybe attached via any heteroatom or carbon atom. Thus, the term includes(but is not limited to) morpholinyl, pyrrolidinonyl, pyrrolidinyl,piperidinyl, hydantoinyl, valerolactamyl, oxiranyl, oxetanyl,tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridinyl,tetrahydroprimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl,tetrahydropyrimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, andthe like.

Representative compounds of this invention include the followingstructure (II) and (III)

wherein, respectively, X corresponds to a carbon and a nitrogen atom.

Thus, representative compounds of this invention include the followingstructures (IIa), (IIb), (IIc), (IId), when X corresponds to a carbonatom

Depending upon the choice of X, the representative compounds of thisinvention include, but are not limited to, the following compounds(Ia-1), (Ib-1), (Ic-1).

Depending upon the choice of X and Y the representative compounds ofthis invention include, but are not limited to, the following compounds(I-1), (I-2), (I-3) and (I-4).

More specific embodiments of the invention include, but are not limitedto, compounds of the formula (I); (II), (III), (IIa), (IIb), (IIc),(IId); (Ia-1), (Ib-1), (Ic-1); (I-1), (I-2), (I-3), (I-4): wherein:

-   -   R₂ and R₃ are not simultaneously hydrogen.

Further specific embodiments of the invention include, but are notlimited to, compounds of the formula (I); (II), (III), (IIa), (IIb),(IIc), (IId); (Ia-1), (Ib-1), (Ic-1); (I-1), (I-2), (I-3), (I-4):wherein:

-   -   R₁ is C1-C3 alkyl group or halo C1-C3 alkyl group, preferably        methyl or trifluoromethyl.

Preferred embodiments of the invention include, but are not limited to,compounds of the formula (I); (II), (III), (IIa), (IIb), (IIc), (IId);(Ia-1), (Ib-1), (Ic-1); (I-1), (I-2), (I-3), (I-4): wherein:

-   -   R₂ and R₃ are not simultaneously hydrogen; and    -   R₁ is C1-C3 alkyl group or halo C1-C3 alkyl group, preferably        methyl or trifluoromethyl;

More preferred embodiments of the invention include, but are not limitedto, compounds of the formula (I); (II), (III), (IIa), (IIb), (IIc),(IId); (Ia-1), (Ib-1), (Ic-1); (I-1), (I-2), (I-3), (I-4): wherein:

-   -   R₂ and R₃ are not simultaneously hydrogen;    -   R₁ is C1-C3 alkyl group or halo C1-C3 alkyl group, preferably        methyl or trifluoromethyl;    -   R is an aryl group selected from: 2,4-dichlorophenyl,        2-chloro-4-methylphenyl, 2-chloro-4-trifluoromethyl,        2-chloro-4-methoxyphenyl, 2,4,5-trimethylphenyl,        2,4-dimethyl-phenyl, 2-methyl-4-methoxyphenyl,        2-methyl-4-chlorophenyl, 2-methyl-4-trifluoromethyl,        2,4-dimethoxyphenyl, 2-methoxy-4-trifluoromethylphenyl,        2-methoxy-4-chlorophenyl, 3-methoxy-4-chlorophenyl,        2,5-dimethoxy-4-chlorophenyl, 2-methoxy-4-isopropylphenyl,        2-methoxy-4-trifluoromethylphenyl, 2-methoxy-4-isopropylphenyl        2-methoxy-4-methylphenyl, 2-trifluoromethyl-4-chlorophenyl,        2,4-trifluoromethylphenyl, 2-trifluoromethyl-4-methylphenyl,        2-trifluoromethyl-4-methoxyphenyl, 2-bromo-4-isopropylphenyl,        4-methyl-6-dimethylaminopyridin-3-yl,        4-dimethylamino-6-methyl-pyridin-3-yl,        6-dimethylamino-pyridin-3-yl and 4-dimethylamino-pyridin-3-yl.

Preferred compounds according to the invention are:

5-(2,4-dichlorophenyl)-1-(1-ethylpropyl)-7-methyl-1,2,2a,3,4,5-hexahydro-1,5,6,8-tetraaza-acenaphthylene(I-1-1);

5-(2,4-dichlorophenyl)-1-(2-ethylbutyl)-7-methyl-1,2,2a,3,4,5,5a,8b-octahydro-1,5,6,8-tetraazaacenaphthylene(I-1-2);

5-(2,4-dichlorophenyl)-1-(2-methoxy-1-methoxymethylethyl)-7-methyl-1,2,2a,3,4,5,5a,8b-octahydro-1,5,6,8-tetraazaacenaphthylene(I-1-3);

7-methyl-1-(1-propylbutyl)-5-[4-(1,1,2-trifluoroethyl)-2-trifluoromethylphenyl]-1,2,2a,3,4,5-hexahydro-1,5,6,8-tetraazaacenaphthylene(I-1-4);

7-methyl-1-(1-propylbutyl)-5-[4-(1,1,2-trifluoroethyl)-2-trifluoromethylphenyl]-1,2,2a(S),-3,4,5-hexahydro-1,5,6,8-tetraazaacanaphthylene;

7-methyl-1-(1-propylbutyl)-5-[4-(1,1,2-trifluoroethyl)-2-trifluoromethylphenyl]-1,2,2a-(R),3,4,5-hexahydro-1,5,6,8-tetraazazcanaphthylene;

5-(2,4-dichlorophenyl)-7-methyl-1-(1-propylbutyl)-1,2,2a,3,4,5-hexahydro-1,5,6,8-tetraaza-acenaphthylene(I-1-5);

5-(2,4-dichlorophenyl)-7-methyl-1-(1-propylbutyl)-1,2,2a-(S),3,4,5,5a,8b-octahydro-1,5,6,8-tetraazaacenaphthylene;

5-(2,4-dichlorophenyl)-7-methyl-1-(1-propylbutyl)-1,2,2a-(R),3,4,5,5a,8b-octahydro-1,5,6,8-tetraazaacenaphthylene;

9-(2,4-dichlorophenyl)-4-(1-ethylpropyl)-2-methyl-5,6,6a,7,8,9-hexahydro-4H-1,3,4-triazaphenalene(isomer 1) and9-(2,4-dichlorophenyl)-4-(1-ethylpropyl)-2-methyl-5,6,6a,7,8,9-hexahydro-4H-1,3,4-triazaphenalene(isomer 2) (2-1-1);

5-cyclopropylmethyl-1-(2,4-dichlorophenyl)-7-methyl-1,2,2a,3,4,5-hexahydro-1,5,6,8-tetraazaacenaphthylene(3-1-1);

1-(2,4-dichlorophenyl)-5-(2-methoxyethyl)-7-methyl-1,2,2a,3,4,5-hexahydro-1,5,6,8-tetraaza-acenaphthylene(3-1-2);

1-(2,4-dichlorophenyl)-5-(1-ethylpropyl)-7-methyl-1,2,2a,3,4,5-hexahydro-1,5,6,8-tetraaza-acenaphthylene(3-1-3);

1-(2,4-dichlorophenyl)-5-(2-ethylbutyl)-7-methyl-1,2,2a,3,4,5-hexahydro-1,5,6,8-tetraaza-acenaphthylene(3-1-4);

1-(2,4-dichlorophenyl)-7-methyl-5-(1-propylbutyl)-1,2,2a,3,4,5-hexahydro-1,5,6,8-tetraaza-acenaphthylene(3-1-5);

7-methyl-5-(1-propylbutyl)-1-[4-(1,1,2-trifluoro-ethyl)-2-trifluoromethylphenyl]-1,2,2a,3,4,5-hexahydro-1,5,6,8-tetraazaacenaphthylene(3-1-6);

5-cyclopropylmethyl-1-(2,4-dichlorophenyl)-7-methyl-4-propyl-1,2,2a,3,4,5-hexahydro-1,5,6,8-tetraazaacenaphthylene(3-1-7);

4-butyl-5-cyclopropylmethyl-1-(2,4-dichlorophenyl)-7-methyl-1,2,2a,3,4,5-hexahydro-1,5,6,8-tetraazaacenaphthylene(3-1-8);

5-cyclopropylmethyl-1-(2,4-dichlorophenyl)-7-methyl-4-propoxy-1,2,2a,3,4,5-hexahydro-1,5,6,8-tetraazaacenaphthylene(3-1-9);

4,5-dibutyl-1-(2,4-dichlorophenyl)-7-methyl-1,2,2a,3,4,5-hexahydro-1,5,6,8-tetraaza-acenaphthylene(3-1-10);

5-(2,4-dichlorophenyl)-1-(1-ethylpropyl)-7-methyl-1,2,2a,3,4,5-hexahydro-1,6,8-triaza-acenaphthylene(4-1-1).

Compounds of formula (I), and salts and solvates thereof, may beprepared by the general methods outlined hereinafter. In the followingdescription, the groups R, R₁, R₂, R₃, R₄, R₅, R₆, X, Y, Z, m, n, p andq have the meaning as previously defined for compounds of formula (I)unless otherwise stated.

Compounds of formula (I) when R₃ is different from hydrogen and m is 1are equivalent to compounds of formula (IV), in which G corresponds tothe previous meanings of R₃ other than hydrogen, may be prepared byreaction of a compound of formula (V),

wherein R₇ is a C1-C4 linear or branched alkyl group and m is 1,equivalent to compounds of formula (VI). Then compounds of formula (VI)may react with the organo-metallic compound GM,

wherein M is a metal to give compounds of formula (IV), optionally inthe presence of a Lewis acid such as borontrifluoride etherate. Suitablemetals for this reaction include lithium, copper or magnesium.

Compounds of formula (I) when R₃ is hydrogen are equivalent to compoundsof formula (Ia), may be prepared by reduction of a compound of formula(V) wherein R₇ is hydrogen and equivalent to compounds of formula (Va),in the presence of an organic acid (e.g. trifluoroacetic). Convenientreducing agents for this reaction are trialkylsilanes (e.g.triethylsilane). The reaction is preferably carried out in an aproticsolvent such as dichloromethane.

Compounds of formula (IIb), corresponding to compounds of formula (II)in which R₃ is hydrogen, may be prepared from compounds of formula (VII)according to the following general Scheme:

wherein L is a leaving group selected in a group consisted fromhalogens, preferably chlorine and reactive residue of sulphonic acid(such as mesylate, triflate) and La represents a suitable reactive groupable to render OLa a good leaving group (such as mesylate, triflate).

The reaction takes place by heating using the amine R₂NH₂ (IX) inexcess, preferably as solvent.

Compounds of formula (VI), may be prepared by oxidation of the allylgroup of compounds of formula (VIII) to the corresponding aldehydefollowed by in situ cyclisation and conversion of the hydroxy group intothe alkoxy group which will be described in details later on.

The oxidation is carried out with osmium tetroxide in the presence ofN-methylmorpholine oxide (NMO), followed by treatment with sodiumperiodate. The reaction is conveniently carried out in a water miscibleorganic solvent such acetone, tetrahydrofuran optionally in the presenceof water.

The conversion of the hydroxy group into C1-C4 alkoxy may be carried outby treatment of the hydroxy group with C1-C4 alcohol in the presence ofa suitable inorganic acid, e.g. hydrochloric acid.

Compounds of formula (VIII) may be prepared by treatment of a compoundof formula (X), with the amine R₂NH₂ (IX).

In an alternative process, compounds of formula (IIa), may be preparedby reaction of a compound of formula (XI),

and when m is 1 it is equivalent to a compound of formula (XIa)

with the amine (IX) in the presence of a suitable reducing agent,followed by in situ cyclisation.

Suitable reducing agents for this reaction include hydride, for examplea borane hydride, or a metal hydride complex like lithium aluminumhydride, borohydride, or an organo-metallic complex such as boranemethyl sulphide, 9-borabicyclononane (9-BBN), triethylsilane, sodiumtriacetoxyborohydride, sodium cyanoborohydride.

Alternatively, boranes may be produced in situ by reacting SodiumBorohydride in the presence of Iodine, an inorganic acid (e.g. sulphoricacid) or an organic acid such as formic acid, trifluoroacetic, aceticacid or methansulphonic acid.

Suitable solvents for this reaction are alcohol (e.g. methanol), ether(e.g. tetrahydrofuran), or halohydrocarbon (e.g. dichloromethane) or anamide (e.g. N,N-dimethylformamide) at a temperature within the range ofroom temperature to the reflux temperature of the reaction mixture.

Compounds of formula (X) wherein Y is nitrogen and X is carbon areequivalent to compounds of formula (Xa), may be obtained from a compoundof formula (XIIa),

equivalent to compounds of formula (XII)

in which X is carbon, La is a suitable reactive group able to render OLaa good leaving group, (such as mesylate) and Ra corresponds to hydrogenor a suitable nitrogen protecting group, if necessary.

Compounds of formula (XIIa) may be subjected to the following reactions:

-   -   i) optionally removal of the nitrogen protecting group Ra; and    -   ii) cyclisation in the presence of organic base such as a        tertiary amine e.g. triethylamine.

These reactions are preferably carried out in an aprotic solvent such asether (e.g. tetrahydrofuran), halohydrocarbon such as dichloromethane oramide such as N,N-dimethylformamide.

Compounds of formula (XII) in which X is carbon and n is 0 areequivalent to compounds of formula (XIIa), may be prepared byintroduction of the suitable reactive group La on a compound of formula(XIII) in which Hal, Ra, n, are defined as above.

Compounds of formula (XIII) may be obtained by reaction of a compound offormula (XV), wherein Rb is a suitable hydroxy protecting group, withamine (XIV), followed by protection of the nitrogen group (if necessary)and removal of hydroxy protecting group.

The reaction with the amine is suitably carried out in an aproticsolvent such as DMF (dimethylformamide) in the presence of a strong base(e.g. sodium hydride).

Compounds of formula (XV) may be prepared by reduction of an ester offormula (XVI) to the corresponding hydroxy with a suitable reducingagent, such as diisobutylaluminumhydride followed by protection of thehydoxy group with a hydroxy suitable protecting group.

Compounds of formula (XVI) may be prepared by reaction of a compound offormula (XVII) with allyl halide (e.g. allyl iodide). The reaction iscarried out in the presence of an organic base such aslithiumhexamethyldisilazane at low temperature and in an aprotic solvent(e.g. tetrahydrofuran).

Compounds of formula (XII) wherein n is 1 and X is carbon are equivalentto compounds of formula (XIIb), may be prepared by reduction of acompound of formula (XVIII), with a suitable reducing agent, e.g. sodiumborohydride in a solvent such as for example an alcohol (e.g. methanol).

Compounds of formula (XVIII) may be prepared by Wittig reaction of acompound of formula (XX) with a phosphorus ylide (XIX), in which R₈ is aphenyl derivative, followed by hydrolysis with an acid (e.g hydrochloricacid). The reaction is carried out in an aprotic solvent such asacetonitrile or an ether such as tetrahydrofuran.

Compounds of formula (XX) may also be prepared by oxidation of acompound of formula (XIII). The oxidation may be carried out using theconventional methods known for converting a hydroxy group into analdehyde group. Thus, for example, the reaction may be carried out usingSwern conditions.

Compounds of formula (X) when Y is carbon and X is carbon are equivalentto compounds of formula (Xb), may be prepared by halogenation of acompound of formula (XXI),

in which, when X and Y are both carbon, is equivalent to a compound offormula (XXIb).

The halogenation reaction may be carried out using conventional methodsknown in the art.

Thus for example the reaction may be carried out by treatment withPO(Hal)₃, wherein within the halogens, chlorine is preferred.

Compounds of formula (XXIb) may be obtained by reaction of acyclohexanone of formula (XXIII), in which R₇ is defined as before, witha salt (e.g hydrochloride) of acetamidine (XXII).

The reaction is carried out in the presence of a C1-C4 alkalinealkoxylate (e.g. sodium methoxylate), in a solvent such as methylalcohol.

Compounds of formula (XXIII) when n is 1 are equivalent to compounds offormula (XXIIIa), may be prepared by reaction of a compound of formula(XXIV) with a silane derivative (XXV), wherein R₇ is as defined before.The reaction is carried out in the presence of Lewis acid and in anorganic solvent.

Compounds of formula (XXIII) when n is 0 are equivalent to compounds offormula (XXIIIb), may be prepared by reaction of a compound of formula(XXVI), in which R7 is defined as before and R7′ has the same meaningsas R7 but not at the same time,

with an organo metallic compound (R₉)₂M (XXVII), in which R₉ is an allylgroup and M is a metal, optionally in the presence of a Lewis acid suchas boron trifluoride etherate. Suitable metals for this reaction includelithium, copper and magnesium.

Compounds of formula (X) when X is nitrogen are equivalent to compoundof formula (Xc), may be prepared by reaction of a compound of formula(XXVIII) with allyl halide (e.g. allyl bromide). The reaction is carriedout in the presence of an inorganic base such as sodium hydride at lowtemperature and in aprotic solvent (e.g. tetrahydrofuran orNN-dimethylformamide).

Compounds of formula (XXVIII) when n is 0 and Y is carbon are equivalentto compounds of formula (XXVIIIa), may be prepared by subjecting acompound of formula (XXIX), in which q is as previously defined,

Compounds of formula (XXIXa), corresponding to compounds (XXIX) in whichq is 1 and Y is carbon, may be subjected to the following reactions:

-   -   i) conversion of the hydroxy group into a suitable leaving group        such as mesylate,    -   ii) conversion of the nitro group into the amine by reduction in        the presence of Na₂S₂O₄ and an inorganic base such as potassium        carbonate and in situ cyclisation.

Compounds of formula (XXIXa), may be prepared by reduction of an estercompound of formula (XXX). The reduction can be conveniently carried outwith sodium borohydride in a protic solvent such alcohol (e.g. methanolor ethanol) and preferably heating e.g. 40-100° C. Compounds of formula(XXX) may be prepared by reaction of a compound of formula (XXXI), withan ester compound (XXXII).

The reaction takes place in an aprotic solvent such as DMF and in thepresence of an inorganic base (i.e. sodium hydride).

Compounds of formula (XXIX) when n is 2 and Y is carbon are equivalentto compounds of formula (XXIXb), may be prepared by reduction ofcompounds of formula (XXXIII) using conventional reducing reagent toconvert aldehyde into alcohol. Thus a suitable reducing agent for thisreaction is sodium borohydride.

Compounds of formula (XXXIII) may be obtained by hydrolysis of enoletherof formula (XXXIV). The reaction is preferably carried out in thepresence of an inorganic acid such as for example hydrogen chloride.Compounds of formula (XXXIV) may be obtained from (XXXV) by Wittigreaction with the ylide (XIX), in the presence of a suitable organicbase like n-BuLi. The reaction is carried out in an aprotic solvent suchas acetonitrile or an ether such as tetrahydrofuran. Compounds offormula (XXXV) may be prepared by oxidation of compounds (XXIXa) when Ycorresponds to carbon, by using conventional methods known to convertalcohol to aldehyde.

Compounds of formula (XI) when R₃ is different from hydrogen areequivalent to compounds of formula (XIb), may be prepared by reaction ofa compound of formula (XI) when R₃ is hydrogen (equivalent to a compoundof formula (XIc)), with the organo metallic compound GMgBr (XXXVI), togive the alcohol compound (XXXVII), which may be oxidised to the ketocompound (XIb) according to the following scheme

Compounds of formula (XIc) when m is 1 are equivalent to compounds offormula (XId), may be prepared by oxidation of a compound of formula(X).

The oxidation reaction is conveniently carried out in the presence ofozone at low temperature e.g. −78° C. in a solvent such asdicholoromethane.

Alternatively, the oxidation takes place by reaction with with osmiumtetraoxide in the presence of N-methyl morpholine oxide (NMO) followedby treatment with sodium periodate. The reaction is conveniently carriedout in a water miscible organic solvent such as acetone ortetrahydrofuran optionally in the presence of water.

Compounds of formula (XIc) when X and Y are carbon, m is 0 and n is 1are equivalent to compounds of formula (XIe), may be prepared bytreating compounds of formula (XXXVIII) with an inorganic base such aspotassium hydroxide in a solvent such as alcohol, followed by reactionwith potassium permanganate. The reaction is suitably carried out inwater.

Compounds of formula (XXXVII), may be prepared by halogenation of acompound of formula (XXXIX). The halogenation reaction may be carried asdescribed above.

Compounds of formula (XXXIX) may be prepared by reaction of a compoundof formula (XL) with a salt (e.g hydrochloric acid) of acetamidine(XXII) using condition as described above. Compounds of formula (XL) maybe prepared by reacting compounds of formula (XXIV), in which R7 is asdefined before, with nitromethane.

Compounds of formula (XIc) when X is carbon, m is 0, n is 1 and Y isnitrogen are equivalent to compounds of formula (XIf), may be preparedby oxidation of a compound of formula (XLI), using conventionaloxidation methods known to convert a hydroxy group into an aldehyde.

Compounds of formula (XLI) may be prepared by subjecting a compound offormula (XLII), wherein La is a suitable leaving group, such asmesylate, Ra and Rb are as defined above, to the following reactions:

-   -   i) optionally, removal of the nitrogen protecting group,    -   ii) cyclisation and    -   iii) removal of the hydroxy protecting group Rb.

Compounds of formula (XLII) may be prepared as discussed before byoxidation of a compound of formula (XLIII), followed by reduction tohydroxy group and conversion in a leaving group.

The oxidation reaction is conveniently carried out in the presence ofozone at low temperature e.g. −78° C. in a solvent such asdichloromethane. The reduction is carried out using sodium borohydrideas reducing agent.

Compounds of formula (XLIII) may be obtained from a compound of formula(XV) with amine (XIV), followed by protection of the nitrogen group.

Compounds of formula (XLI) may be converted to compounds of formula(VIIa), corresponding to compounds of formula (VII) in which X iscarbon, Y is nitrogen m and n are 1, according to known methods.

According to a previous Scheme, compounds of formula (VIIa) may beconverted to compound of formula (I-1a), corresponding to compound offormula (I-1) in which R₃ is hydrogen.

Compounds of formula (Xc) in which X and Y are nitrogen and n is 1 areequivalent to compounds of formula (Xc′), may be prepared by reaction ofa compound of formula (XLIV) with dibromoethane, in the presence of anorganic or inorganic base. The reaction is suitably carried out in anaprotic solvent such as NN-dimethylformamide or acetonitrile.

Compounds of formula (XLIV) may be prepared by compounds of formula(XLV) by treatment with iron and an inorganic acid e.g. hydrochloricacid. Compounds of formula (XLV) may be prepared by reaction of compound(XXXI) and the amine (XIV).

Compounds of formula (XVII), (XXIV), (XXVI) and (XXXI) are either knowncompounds or may be prepared by analogous method to those described forknown compounds.

In summary, compounds of formula (I-1a), may be prepared according tothe following Scheme 1:

in which Hal, R, R₁, R₇, R₂, La, Ra and Rb are defined as above andpreferably R₇ is a methyl group, Hal is chlorine, Ra is t-butylcarbonyl,Rb is t-BuPh₂ Si derivative, OLa is a mesyl group and

-   -   step a stands for allylation with allyl iodide at 0° C. in basic        conditions (e.g. LiHMDS); the starting material may be prepared        in similar way to what described in Wayne G. C. et al., J.        Prakt. Chem., (2000), 342(5), 504-7;    -   step b stands for reduction of the ester group with a suitable        reducing agent, e.g. DIBAl-H, in usual conditions (CH₂Cl₂, 0° C.        to r.t.);    -   step c stands for protection of the hydroxy group, preferably        with t-BuPh₂SiCl, in DMF with DMAP as catalyst (0° C. to r.t);    -   step d stands for reaction with the amine RNH₂ (XIV) as        described above;    -   step e stands for protection of the amino group with a suitale        protecting group, for example by treatment with (BOC)₂O in        presence of DMAP;    -   step f stands for, i) oxidation with OsO₄ in acetone/water,        then ii) treatment with NaIO₄ in THF/water, and finally iii)        reduction with NaBH₄ in a suitable solvent (e.g. EtOH);    -   step g stands for deprotection of the amino protecting group        (e.g. CF₃CO₂H in CH₂Cl₂);    -   step h stands for intramolecular cyclisation, for example by        mesylation of the hydroxy group in basic conditions (i.e. Et₃N);    -   step i stands for deprotection of the hydroxy protecting group        (e.g. Et₃N-3HF in DMF at 40° C.);    -   step j stands for transformation of the hydroxy group in a        suitable leaving group (e.g. mesylation);    -   step k stands for reaction with the amine (IX) as described        above.

Alternatively, the synthesis can be modified following the steps below(starting from an already described intermediate) according to Scheme 2

in which

-   -   step l stands for the first two reactions of previous step f,        and    -   step m stands for treatment with Et₃SiH in the presence of        BF₃-Et₂O.

The synthesis is then completed as described in Scheme 1.

In another alternative, the protection of the amino group can be avoidedthrough the following sequence of steps (starting from an alreadydescribed intermediate) according to scheme 2a

in wich

-   -   step n corresponds to previous step f);    -   step o corresponds to previous step j);    -   step p stands for reaction with the amine RNH₂ (XIV) as        described above;

The synthesis is then completed as described in Scheme 1.

In another embodiment of the invention, compounds of formula (I-2), inwhich R3 is hydrogen are equivalent to compounds of formula (I-2a), maybe prepared according to the following Scheme 3

in which Hal, R, R₁, R₂, R₇, Rb are defined as above and preferably R₇is a methyl group, Hal is chlorine, Rb is t-BuPh₂ Si derivative, OLa isa mesyl group and

-   -   step a′ stands for esterification in usual conditions (R₇H, acid        catalyst, reflux);    -   step b′ stands for alkylation with the suitable alkylating agent        (e.g. methyl 5-iodovalerate in the presence of LiHMDS);    -   step c′ stands for intramolecular cyclisation in basic        conditions (i.e. MeONa, refluxing toluene);    -   step d′ stands for phenylselenylation followed by oxidation with        H₂O₂ and subsequent elimination;    -   step e′ stands for 1,4-carbonyl addition with a suitable silane        such as allyltrimethylsilane catalysed by TiCl₄;    -   step f′ stands for reaction with the amidine (XXII) as described        above;    -   step g′ stands for halogenation of the hydroxy group (e.g. by        treatment with POCl₃ at reflux);    -   step h′ stands for oxidative cleavage of the double bond by, for        example, ozonization;    -   step i′ stands for reductive amination in the presence of        NaBH₃CN with the amine (IX) and subsequent intramolecular        cyclisation.

In a further embodiment of the invention, compounds of formula (I-3) inwhich R₃ is hydrogen are equivalent to compounds of formula (I-3a) maybe prepared according to Scheme 4

in which

-   -   step a″ stands for protection of the amino group with a suitale        protecting group, for example by treatment with (BOC)₂O in        presence of DMAP;    -   step b″ corresponds to previous step i);    -   step c″ stands for mesylation of the hydroxy group in basic        conditions (i.e. Et₃N);    -   step d″ stands for deprotection of the protective group of the        amino, e.g. by treatment with TFA and then subsequent        cyclisation in basic conditions, e.g. Et₃N;    -   step e″ corresponds to previous step h′) or corresponds to        previous step l);    -   step f″ corresponds to previous step i′);

In another alternative, the last stages of the synthesis could be doneas follow and compounds of formula (I-3) in which R₃ is different fromhydrogen corresponding to compounds of formula (I-3b) according toScheme 5

in which

-   -   step a′″ corresponds to previous step k);    -   step b′″ corresponds to previous step l);    -   step c′″ stands for reduction, e.g. by treatment with Et₃SiH,        TFA;    -   step d″′ stands for formation of the ether group, e.g. by        treatment with methanol in presence of PTSA;    -   step e′″ stands for reaction with an organo-metallic compound,        such as R₃Cu in presence of BF₃.Et₂O.

Alternatively compounds of formula (I-3a), when it is not necessary toprotect the amino group, may be prepared as exemplified below in Scheme6, starting from an already known intermediate:

wherein

-   -   step a″″ corresponds to previous step i);    -   step b″″ corresponds to previous step j), followed by in situ        intramolecular cyclisation;    -   step c″″ corresponds to previous step f);    -   step d″″ corresponds to previous steps j) and k).

In another embodiment of the invention, compounds of formula (I-4) whenR₃ is hydrogen corresponding to compounds of formula (I-4a) may beprepared according to Scheme 7

in which

-   -   step a′″″ stands for reaction with nitromethane in usual        conditions;    -   step b′″″ stands for reaction with the amidine (XXII) as        described above;    -   step c′″″ corresponds to previous step g′);    -   step d′″″ stands for formation of the aldehyde group, e.g. by        treatment with KOH in methanol and subsequent oxidation by        KMnO₄;    -   step e′″″ corresponds to previous step i′).

Examples of suitable nitrogen protecting group include alkoxycarbonyl,e.g. t-butoxycarbonyl and arylsulphonyl, e.g phenylsulphonyl.

In any of the above reaction the nitrogen protecting group may beremoved by conventional procedures known for removing such groups (suchas those described in Protective Groups in Organic Chemistry, pages46-119, Edited by J F W McOmie (Plenum Press, 1973)). Thus, when Ra isalkoxycarbonyl, the group may be removed by acid hydrolisis using forexample trifluoro acetic acid.

Examples of suitable hydroxy protecting group include trihydrocarbylsilyl ethers such as the trimethylsilyl or t-butyldimethylsilyl ether.

The hydroxyl protecting groups may be removed by well-known standardprocedures (such as those described in Protective Groups in OrganicChemistry, pages 46-119, Edited by J F W McOmie (Plenum Press, 1973)).For example when Rb is a t-butyldimethylsilyl group, this may be removedby treatment with triethylamine trihydrofluoride.

Pharmaceutical acceptable salts may also be prepared from other salts,including other pharmaceutically acceptable salts, of the compound offormula (I) using conventional methods.

The compounds of formula (I) may readily be isolated in association withsolvent molecules by crystallisation or evaporation of an appropriatesolvent to give the corresponding solvates.

When a specific enantiomer of a compound of general formula (I) isrequired, this may be obtained for example by resolution of acorresponding enantiomeric mixture of a compound of formula (I) usingconventional methods. Thus the required enantiomer may be obtained fromthe racemic compound of formula (I) by use of chiral HPLC procedure.

The subject invention also includes isotopically-labeled compounds,which are identical to those recited in formulas I and following, butfor the fact that one or more atoms are replaced by an atom having anatomic mass or mass number different from the atomic mass or mass numberusually found in nature. Examples of isotopes that can be incorporatedinto compounds of the invention include isotopes of hydrogen, carbon,nitrogen, oxygen, phosphorous, fluorine, iodine, and chlorine, such as³H, ¹¹C, ¹⁴C, ¹⁸F, ¹²³I and ¹²⁵I.

Compounds of the present invention and pharmaceutically acceptable saltsof said compounds that contain the aforementioned isotopes and/or otherisotopes of other atoms are within the scope of the present invention.Isotopically —labeled compounds of the present invention, for examplethose into which radioactive isotopes such as ³H, ¹⁴C are incorporated,are useful in drug and/or substrate tissue distribution assays.Tritiated, i.e., ³H, and carbon-14, i.e., ¹⁴C, isotopes are particularlypreferred for their ease of preparation and detectability. ¹¹C and ⁸Fisotopes are particularly useful in PET (positron emission tomography),and ¹²⁵I are particularly useful in SPECT (single photon emissioncomputerized tomography), all useful in brain imaging. Further,substitution with heavier isotopes such as deuterium, i.e., ²H, canafford certain therapeutic advantages resulting from greater metabolicstability, for example increased in vivo half-life or reduced dosagerequirements and, hence, may be preferred in some circumstances.Isotopically labeled compounds of formula I and following of thisinvention can generally be prepared by carrying out the proceduresdisclosed in the Schemes and/or in the Examples below, by substituting areadily available isotopically labeled reagent for a non-isotopicallylabeled reagen.

The CRF receptor antagonists of the present invention demonstrateactivity at the CRF receptor site including CRF 1 and CRF 2 receptorsand may be used in the treatment of conditions mediated by CRF or CRFreceptors.

The effectiveness of a compound as a CRF receptor antagonist may bedetermined by various assay methods. Suitable CRF antagonists of thisinvention are capable of inhibiting the specific binding of CRF to itsreceptor and antagonizing activities associated with CRF. A compound ofstructure (I) may be assessed for activity as a CRF antagonist by one ormore generally accepted assays for this purpose, including (but notlimited to) the assays disclosed by DeSouza et al. (J. Neuroscience 7:88, 1987) and Battaglia et al. (Synapse 1: 572, 1987).

The CRF receptors-binding assay was performed by using the homogeneoustechnique of scintillation proximity (SPA). The ligand binds torecombinant membrane preparation expressing the CRF receptors which inturn bind to wheatgerm agglutinin coated SPA beads.

In the Experimental Part will be disclosed the details of theexperiments.

With reference to CRF receptor binding affmities, CRF receptorantagonists of this invention have a Ki less than 10 μm. In a preferredembodiment of this invention, a CRF receptor antagonist has a Ki of lessthan 10 μm.

In a more preferred embodiment the value of Ki is less than 1 μm andmore preferably less than 0.1 μm. As set forth in greater detail below,the Ki values of representative compounds of this invention were assayedby the methods set forth in Example 5.

Preferred compounds having a Ki of less than 1 μm are compound numbers3-1-3 and 3-1-10.

More preferred compounds having a Ki less than 0.1 μm are compoundnumbers 1-1-1, 1-1-4, 1-1-5, 1-2-1, 3-1-5, and 3-1-6.

Compounds of the invention may be useful in the treatment of centralnervous system disorders where CRF receptors are involved. In particularin the treatment or prevention of major depressive disorders includingbipolar depression, unipolar depression, single or recurrent majordepressive episodes with or without psychotic features, catatonicfeatures, melancholic features, atypical features or postpartum onset,the treatment of anxiety and the treatment of panic disorders. Othermood disorders encompassed within the term major depressive disordersinclude dysthymic disorder with early or late onset and with or withoutatypical features, neurotic depression, post traumatic stress disordersand social phobia; dementia of the Alzheimer's type, with early or lateonset, with depressed mood; vascular dementia with depressed mood; mooddisorders induced by alcohol, amphetamines, cocaine, hallucinogens,inhalants, opioids, phencyclidine, sedatives, hypnotics, anxiolytics andother substances; schizoaffective disorder of the depressed type; andadjustment disorder with depressed mood. Major depressive disorders mayalso result from a general medical condition including, but not limitedto, myocardial infarction, diabetes, miscarriage or abortion, etc.

Compounds of the invention are useful as analgesics. In particular theyare useful in the treatment of traumatic pain such as postoperativepain; traumatic avulsion pain such as brachial plexus; chronic pain suchas arthritic pain such as occurring in osteo-, rheumatoid or psoriaticarthritis; neuropathic pain such as post-herpetic neuralgia, trigeminalneuralgia, segmental or intercostal neuralgia, fibromyalgia, causalgia,peripheral neuropathy, diabetic neuropathy, chemotherapy-inducedneuropathy, AIDS related neuropathy, occipital neuralgia, geniculateneuralgia, glossopharyngeal neuralgia, reflex sympathetic dystrophy,phantom limb pain; various forms of headache such as migraine, acute orchronic tension headache, temporomandibular pain, maxillary sinus pain,cluster headache; odontalgia; cancer pain; pain of visceral origin;gastrointestinal pain; nerve entrapment pain; sport's injury pain;dysmennorrhoea; menstrual pain; meningitis; arachnoiditis;musculoskeletal pain; low back pain e.g. spinal stenosis; prolapseddisc; sciatica; angina; ankylosing spondyolitis; gout; burns; scar pain;itch; and thalamic pain such as post stroke thalamic pain.

Compounds of the invention are also useful for the treatment ofdysfunction of appetite and food intake and in circumstances such asanorexia, anorexia nervosa and bulimia.

Compounds of the invention are also useful in the treatment of sleepdisorders including dysomnia, insomnia, sleep apnea, narcolepsy, andcircadian ritmic disorders.

Compounds of the invention are also useful in the treatment orprevention of cognitive disorders. Cognitive disorders include dementia,amnestic disorders and cognitive disorders not otherwise specified.

Furthermore compounds of the invention are also useful as memory and/orcognition enhancers in healthy humans with no cognitive and/or memorydeficit.

Compounds of the invention are also useful in the treatment of toleranceto and dependence on a number of substances. For example, they areuseful in the treatment of dependence on nicotine, alcohol, caffeine,phencyclidine (phencyclidine like compounds), or in the treatment oftolerance to and dependence on opiates (e.g. cannabis, heroin, morphine)or benzodiazepines; in the treatment of cocaine, sedative ipnotic,amphetamine or amphetamine-related drugs (e.g. dextroamphetamine,methylamphetamine) addiction or a combination thereof.

Compounds of the invention are also useful as anti-inflammatory agents.In particular they are useful in the treatment of inflammation inasthma, influenza, chronic bronchitis and rheumatoid arthritis; in thetreatment of inflammatory diseases of the gastrointestinal tract such asCrohn's disease, ulcerative colitis, inflammatory bowel disease (IBD)and non-steroidal anti-inflammatory drug induced damage; inflammatorydiseases of the skin such as herpes and eczema; inflammatory diseases ofthe bladder such as cystitis and urge incontinence; and eye and dentalinflammation.

Compounds of the invention are also useful in the treatment of allergicdisorders, in particular allergic disorders of the skin such asurticaria, and allergic disorders of the airways such as rhinitis.

Compounds of the invention are also useful in the treatment of emesis,i.e. nausea, retching and vomiting. Emesis includes acute emesis,delayed emesis and anticipatory emesis. The compounds of the inventionare useful in the treatment of emesis however induced. For example,emesis may be induced by drugs such as cancer chemotherapeutic agentssuch as alkylating agents, e.g. cyclophosphamide, carmustine, lomustineand chlorambucil; cytotoxic antibiotics, e.g. dactinomycin, doxorubicin,mitomycin-C and bleomycin; anti-metabolites, e.g. cytarabine,methotrexate and 5-fluorouracil; vinca alkaloids, e.g. etoposide,vinblastine and vincristine; and others such as cisplatin, dacarbazine,procarbazine and hydroxyurea; and combinations thereof; radiationsickness; radiation therapy, e.g. irradiation of the thorax or abdomen,such as in the treatment of cancer; poisons; toxins such as toxinscaused by metabolic disorders or by infection, e.g. gastritis, orreleased during bacterial or viral gastrointestinal infection;pregnancy; vestibular disorders, such as motion sickness, vertigo,dizziness and Meniere's disease; post-operative sickness;gastrointestinal obstruction; reduced gastrointestinal motility;visceral pain, e.g. myocardial infarction or peritonitis; migraine;increased intercranial pressure; decreased intercranial pressure (e.g.altitude sickness); opioid analgesics, such as morphine; andgastro-oesophageal reflux disease, acid indigestion, over-indulgence offood or drink, acid stomach, sour stomach, waterbrash/regurgitation,heartburn, such as episodic heartburn, nocturnal heartburn, andmeal-induced heartburn and dyspepsia.

Compounds of the invention are of particular use in the treatment ofgastrointestinal disorders such as irritable bowel syndrome (IBS); skindisorders such as psoriasis, pruritis and sunburn; vasospastic diseasessuch as angina, vascular headache and Reynaud's disease; cerebralischeamia such as cerebral vasospasm following subarachnoid haemorrhage;fibrosing and collagen diseases such as scleroderma and eosinophilicfascioliasis; disorders related to immune enhancement or suppressionsuch as systemic lupus erythematosus and rheumatic diseases such asfibrositis; and cough.

Compounds of the invention are useful for the treatment of neurotoxicinjury which follows cerebral stroke, thromboembolic stroke, hemorrhagicstroke, cerebral ischemia, cerebral vasospam, hypoglycemia, hypoxia,anoxia, perinatal asphyxia cardiac arrest.

The invention therefore provides a compound of formula (I) or apharmaceutically acceptable salt or solvate thereof for use in therapy,in particular in human medicine.

There is also provided as a further aspect of the invention the use of acompound of formula (I) or a pharmaceutically acceptable salt or solvatethereof in the preparation of a medicament for use in the treatment ofconditions mediated by CRF.

In an alternative or further aspect there is provided a method for thetreatment of a mammal, including man, in particular in the treatment ofcondition mediated by CRF, comprising administration of an effectiveamount of a compound of formula (I) or a pharmaceutically acceptablesalt or a solvate thereof.

It will be appreciated that reference to treatment is intended toinclude prophylaxis as well as the alleviation of established symptoms.

Compounds of formula (I) may be administered as the raw chemical but theactive ingredient is preferably presented as a pharmaceuticalformulation.

Accordingly, the invention also provides a pharmaceutical compositionwhich comprises at least one compound of formula (I) or apharmaceutically acceptable salt thereof and formulated foradministration by any convenient route. Such compositions are preferablyin a form adapted for use in medicine, in particular human medicine, andcan conveniently be formulated in a conventional manner using one ormore pharmaceutically acceptable carriers or excipients.

Thus compounds of formula (I) may be formulated for oral, buccal,parenteral, topical (including ophthalmic and nasal), depot or rectaladministration or in a form suitable for administration by inhalation orinsufflation (either through the mouth or nose).

For oral administration, the pharmaceutical compositions may take theform of, for example, tablets or capsules prepared by conventional meanswith pharmaceutically acceptable excipients such as binding agents (e.g.pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropylmethylcellulose); fillers (e.g. lactose, microcrystalline cellulose orcalcium hydrogen phosphate); lubricants (e.g. magnesium stearate, talcor silica); disintegrants (e.g. potato starch or sodium starchglycollate); or wetting agents (e.g. sodium lauryl sulphate). Thetablets may be coated by methods well known in the art. Liquidpreparations for oral administration may take the form of, for example,solutions, syrups or suspensions, or they may be presented as a dryproduct for constitution with water or other suitable vehicle beforeuse. Such liquid preparations may be prepared by conventional means withpharmaceutically acceptable additives such as suspending agents (e.g.sorbitol syrup, cellulose derivatives or hydrogenated edible fats);emulsifying agents (e.g. lecithin or acacia); non-aqueous vehicles (e.g.almond oil, oily esters, ethyl alcohol or fractionated vegetable oils);and preservatives (e.g. methyl or propyl-p-hydroxybenzoates or sorbicacid). The preparations may also contain buffer salts, flavouring,colouring and sweetening agents as appropriate.

Preparations for oral administration may be suitably formulated to givecontrolled release of the active compound.

For buccal administration the composition may take the form of tabletsor formulated in conventional manner.

The compounds of the invention may be formulated for parenteraladministration by bolus injection or continuous infusion. Formulationsfor injection may be presented in unit dosage form e.g. in ampoules orin multi-dose containers, with an added preservative. The compositionsmay take such forms as suspensions, solutions or emulsions in oily oraqueous vehicles, and may contain formulatory agents such as suspending,stabilising and/or dispersing agents. Alternatively, the activeingredient may be in powder form for constitution with a suitablevehicle, e.g. sterile pyrogen-free water, before use.

The compounds of the invention may be formulated for topicaladministration in the form of ointments, creams, gels, lotions,pessaries, aerosols or drops (e.g. eye, ear or nose drops). Ointmentsand creams may, for example, be formulated with an aqueous or oily basewith the addition of suitable thickening and/or gelling agents.Ointments for administration to the eye may be manufactured in a sterilemanner using sterilised components.

Lotions may be formulated with an aqueous or oily base and will ingeneral also contain one or more emulsifying agents, stabilising agents,dispersing agents, suspending agents, thickening agents, or colouringagents. Drops may be formulated with an aqueous or non-aqueous base alsocomprising one or more dispersing agents, stabilising agents,solubilising agents or suspending agents. They may also contain apreservative.

The compounds of the invention may also be formulated in rectalcompositions such as suppositories or retention enemas, e.g. containingconventional suppository bases such as cocoa butter or other glycerides.

The compounds of the invention may also be formulated as depotpreparations. Such long acting formulations may be administered byimplantation (for example subcutaneously or intramuscularly) or byintramuscular injection. Thus, for example, the compounds of theinvention may be formulated with suitable polymeric or hydrophobicmaterials (for example as an emulsion in an acceptable oil) or ionexchange resins, or as sparingly soluble derivatives, for example, as asparingly soluble salt.

For intranasal administration, the compounds of the invention may beformulated as solutions for administration via a suitable metered orunitary dose device or alternatively as a powder mix with a suitablecarrier for administration using a suitable delivery device.

A proposed dose of the compounds of the invention is 1 to about 1000 mgper day. It will be appreciated that it may be necessary to make routinevariations to the dosage, depending on the age and condition of thepatient and the precise dosage will be ultimately at the discretion ofthe attendant physician or veterinarian. The dosage will also depend onthe route of administration and the particular compound selected.

Thus for parenteral administration a daily dose will typically be in therange of 1 to about 100 mg, preferably 1 to 80 mg per day. For oraladministration a daily dose will typically be within the range 1 to 300mg e.g. 1 to 100 mg.

EXAMPLES

In the Intermediates and Examples unless otherwise stated:

Melting points (m.p.) were determined on a Gallenkamp m.p. apparatus andare uncorrected. All temperatures refers to ° C. Infrared spectra weremeasured on a FT-IR instrument. Proton Magnetic Resonance (¹H-NMR)spectra were recorded at 400 MHz, chemical shifts are reported in ppmdownfield (d) from Me₄Si, used as internal standard, and are assigned assinglets (s), doublets (d), doublets of doublets (dd), triplets (t),quartets (q) or multiplets (m). Column chromathography was carried outover silica gel (Merck AG Darmstaadt, Germany). The followingabbreviations are used in text: EtOAc=ethyl acetate, cHex=cyclohexane,CH₂Cl₂=dichloromethane, Et₂O=dietyl ether, DMF=N,N-dimethylformamide,DIPEA=N,N-diisopropylethylamine, MeOH=methanol, Et₃N=triethylamine,TFA=trifluoroacetic acid, THF=tetrahydrofuran,DIBAL-H=diisobutylaluminium hydride, DMAP=dimethylaminopyridine,LHMDS=lithium hexamethyldisilazane; Tlc refers to thin layerchromatography on silica plates, and dried refers to a solution driedover anhydrous sodium sulphate; r.t. (RT) refers to room temperature.

Intermediate 1

(4,6-Dichloro-2-methyl-pyrimidin-5-yl)-acetic acid methyl ester

Sodium (1.74 g) was added portionwise to anh. MeOH (60 mL), at 0° C.,under N₂. After consumption of metallic sodium, acetamidinehydrochloride (7.06 g) was added. After 20 min of stirring, theprecipitated NaCl was filtered off. A solution of2-ethoxycarbonyl-succinic acid diethyl ester (6.04 g) in anh. MeOH (20mL) was added to the solution of free acetamidine and the mixture wasstirred at r.t. for 2 days. The reaction mixture was concentrated todryness in vacuo and the yellow foam (8.69 g) obtained was then mixedwith POCl₃ (70 mL) and heated at reflux for 3.5 hr. The resultingsolution was cooled to r.t. and poured slowly into ice/water (600 mL)and NH₄OH (50 mL) with vigorous stirring. The product was extracted withEtOAc (3×50 mL) and with Et₂O (3×20 mL). The combined organic extractswere washed with H₂O (60 mL) and brine (40 mL), dried over Na₂SO₄,filtered and concentrated in vacuo. The crude oil was purified by flashchromatography (silica gel, cHex/EtOAc 9:1) to give the title compoundas a yellow solid (4.27 g).

NMR (¹H, CDCl₃): δ 5.85 (m, 1H), 5.15 (dq, 1H), 5.11 (dq, 1H), 3.61 (dt,2H), 2.67 (s, 3H).

MS (m/z): 202 [M]⁺.2Cl; 167 [MH−Cl]⁺,1Cl.

Intermediate 2

2-(4,6-Dichloro-2-methyl-pyrimidin-5-yl)-pent-4-enoic acid methyl ester

A solution of intermediate 1 (1.33 g, 5.68 mmol) in anh. THF (8 mL),under N₂, was treated with lithium bis(trimethylsilyl) amide (1Msolution in hexane, 11.5 mL, 2 eq,) at 0° C. for 15 min beforeallylbromide (0.99 mL, 2 eq) was added. The mixture was stirred for 4 hrat r.t. and quenched with water (20 mL). The product was extracted withEtOAc (2×15 mL) and the organic phase was washed with H₂O (2×15 mL) andwith brine (1×15 mL), dried over Na₂SO₄ and concentrated in vacuo. Thecrude product was purified by flash chromatography (silica gel,EtOAc/cHex 1:9) to give the title compound (673.8 mg) as a white solid.

NMR (¹H, CDCl₃): δ 5.77 (m, 1H), 5.03 (m, 2H), 4.43 (dd, 1H), 3.76 (s,3H), 3.12 (m, 1H), 2.78 (m, 1H), 2.73 (s, 3H).

MS (m/z): 374[M]+2Cl.

Intermediate 3

2-(4,6-Dichloro-2-methyl-pyrimidin-5-yl)-pent-4-en-1-ol

To a solution of intermediate 2 (257 mg) in anh. CH₂Cl₂ (9.3 mL), at−78° C., under N₂, was added DIBAl-H (1M solution in hexane, 5.6 mL, 6eq). After the addition was complete the reaction mixture was stirred at−78° C. for 1 hr and at 0° C. for 2 hr. The reaction mixture was pouredinto a solution of HCl 0.5N in ice (20 mL) and extracted with CH₂Cl₂(3×10 mL). The combined organic extracts were dried over anh. Na₂SO₄,filtered and concentrated in vacuo to give the title compound (200 mg)as a colourless oil.

NMR (¹H, CDCl₃): δ 5.76 (m, 1H), 5.12 (m, 1H), 5.01 (m, 1H), 4.16 (m,1H), 4.06 (m, 1H), 3.91 (m, 1H), 2.8-2.6 (m, 2H), 2.70 (s, 3H), 1.50 (t,1H).

MS (m/z): 247 [M]⁺, 2Cl.

Intermediate 4

5-[1-(tert-Butyl-dimethyl-silanyloxymethyl)-but-3-enyl]-4,6-dichloro-2-methylpyrimidine

To a solution of intermediate 3 (200 mg) in anh. DMF (12 mL), at 0° C.,under N₂, was added tert-butyl-dimethylsilylchloride (245 mg, 2 eq) andimidazole (553 mg, 10 eq). The reaction was stirred at r.t. for 2 hr andmore tert-butyl-dimethylsilylchloride (61 mg, 0.5 eq) was added. After 1hr, sat.aq. NH₄Cl (15 mL) and EtOAc (15 mL) were added and the aqueosphase was extracted with additional EtOAc (2×15 mL). The combinedextracts were washed with H₂O (10 mL), dried over anh. Na₂SO₄, filteredand concentrated in vacuo. The crude product was purified by flashchromatography (silica gel, cHex/EtOAc 19:1) to give the title compound(237 mg) as a colorless oil.

NMR (¹H, CDCl₃): δ 5.72 (m, 1H), 5.10 (d, 1H), 4.98 (d, 1H), 4.11 (m,1H), 3.94 (m, 2H), 2.69 (s, 3H), 2.6-2.7 (m, 2H), 0.82 (s, 9H), 0.05 (s,3H), 0.01 (s, 3H).

MS (m/z): 361 [M]⁺, 2Cl.

Intermediate 5

{5-[1-(tert-Butyl-dimethyl-silanyloxymethyl)-but-3-enyl]-6-chloro-2-methyl-pyrimidin-4-yl}-(2,4-dichlorophenyl)amine

A solution of 2,4-dichloro-aniline (192 mg) in anh. THF (12 mL), underN₂, was treated with sodium hydride (80% in mineral oil, 393 mg) at 0°C. for 15 min and then intermediate 4 (434 mg, 1.19 mmol) in anh. THF (4mL) was added. The mixture was heated to reflux for 3 hr and quenchedwith water (20 mL). The product was extracted with EtOAc (2×20 mL),dried over anh. Na₂SO₄ and concentrated in vacuo. The crude product waspurified by flash chromatography (silica gel, EtOAc/cHex 9:1) to givethe title compound (419 mg) as a yellow oil.

NMR (¹H, CDCl₃), T=55° C.: δ 8.35 (bs, 1H), 8.13 (bd, 2H), 7.42 (d, 1H),7.25 (dd, 1H), 5.73 (m, 1H), 5.03 (m, 2H), 4.10 (dd, 1H), 3.99 (dd, 1H),3.65 (bm, 1H), 2.75 (m, 2H), 2.47 (s, 3H), 0.82 (s, 9H), 0.01 (s, 3H),0.00 (s, 3H).

MS (m/z): 486 [MH]⁺, 3Cl.

Intermediate 6

{5-[1-(tert-Butyl-dimethyl-silanyloxymethyl)-but-3-enyl]-6-chloro-2-methyl-pyrimidin-4-yl}-(2,4-dichlorophenyl)-carbamicacid tert-butyl ester

To a solution of intermediate 5 (419 mg) in anh. CH₂Cl₂ (17 mL), underN₂, was added (BOC)₂O (376 mg, 2 eq) and DMAP (cat). The reactionmixture was stirred at r.t. for 18 hr. The solution was diluted withwater (10 ML) and extracted with EtOAc (3×15 mL). The combined organicextracts were dried over anh. Na₂SO₄, filtered and concentrated todryness in vacuo. Flash chromatography of the crude product (silica gel,cHex/EtOAc 9:1) gave the title compound (420 mg) as a yellow solid.

NMR (¹H, CDCl₃, 40° C.): δ 7.47 (d, 1H), 7.30 (d, 1H), 7.14 (dd, 1H),5.66 (m, 1H), 5.03-4.89 (m, 2H), 3.98-3.8 (m, 2H), 3.43 (b, 1H), 2.8-2.6(m, 2H), 2.56 (bs, 3H), 1.41 (s, 9H), 0.77 (s, 9H), −0.02 (s, 3H), −0.10(s, 3H).

IR (nujol, cm⁻¹): 1716.

MS (m/z): 588 [MH]^(+,), 3Cl.

Intermediate 7

[6-Chloro-5-(1-hydroxymethyl-but-3-enyl)-2-methyl-pyrimidin-4-yl]-(2,4-dichlorophenyl)-carbamicacid tert-butyl ester

To a solution of intermediate 6 (50 mg) in anh. DMF (1 mL), under N₂,was added TEA-3HF (21 μl, 1.5 eq). The reaction was stirred at r.t. for18 hr. The solution was diluted with water (10 mL) and extracted withEtOAc (3×15 mL). The combined organic extracts were dried over anh.Na₂SO₄, filtered and concentrated to dryness in vacuo. Flashchromatography of the crude product (silica gel, cHex/EtOAc 8:2) gavethe title compound (30 mg) as colourless oil.

NMR (¹H, DMSO, T=70° C.): δ 7.69 (d, 1H), 7.43-7.33 (m, 2H), 5.64 (m,1H), 5.00-4.88 (m, 2H), 4.54 (1H, m), 3.71 (m, 2H), 3.29 (m, 1H), 2.66(m, 2H), 2.5 (s, 3H), 1.31 (s, 9H).

MS (m/z): 472 [MH]⁺, 3Cl.

Intermediate 8

Methanesulfonic acid2-{4-[tert-butoxycarbonyl-(2,4-dichlorophenyl)-amino]-6-chloro-2-methyl-pyrimidin-5-yl}-pent-4-enylester

To a solution of intermediate 7 (130 mg) in anh. CH₂Cl₂ (5.52 mL), atr.t, under N₂, was added Et₃N (192 μl, 5 eq) and CH₃SO₂Cl (43 μl, 2 eq).The reaction was stirred at r.t. for 18 hr. The reaction mixture wasdiluted with water (20 mL) and extracted with EtOAc (3×25 mL). Thecombined organic extracts were dried over anh. Na₂SO₄, filtered andconcentrated in vacuo. The crude product was purified by flashchromatography (silica gel, cHex/EtOAc 8:2) to give the title compound(148 mg) as a colourless oil.

NMR (¹H, DMSO, T=70° C.): δ 7.72 (d, 1H), 7.36 (dd, 1H), 7.28 (d, 1H),5.56 (m, 1H), 5.00 (d, 1H), 4.92 (d, 1H), 4.46 (m, 2H), 3.51 (m, 1H),3.02 (s, 3H), 2.65 (m, 1H), 2.54 (s, 3H), 2.50 (m, 1H), 1.38 (s, 9H).

IR (cm⁻¹): 1725, 1641, 1362

MS (m/z): 550 [MH]⁺, 3Cl

Intermediate 9

5-Allyl-4-chloro-7-(2,4-dichlorophenyl)-2-methyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine

A solution of intermediate 8 (120 mg) in TFA 20%/CH₂Cl₂ (7 mL) wasstirred at r.t. for 2 hr. To remove TFA, the solvent of the reactionmixture was evaporated in vacuo and repeated additions of CH₂Cl₂ andevaporation were made. The crude intermediate was then dissolved in anh.THF (5 mL) and Et₃N (284 μl, 5 eq) was added. After 1 hr of stirring atr.t., H₂O was added and the aqueous layer was extracted with EtOAc (3×10mL). The combined organic extracts were dried over anh. Na₂SO₄, filteredand concentrated to dryness in vacuo to give the title compound (124 mg)as a colourless oil.

NMR (¹H, CDCl₃): δ 7.49 (dd, 1H), 7.30 (d+s, 2H), 5.77 (m, 1H),5.16-5.12 (m, 2H), 4.00 (t, 1H), 3.77 (m, 1H), 3.57 (m, 1H), 2.7 (m,1H), 2.47 (m, 1H), 2.45 (s, 3H).

MS (m/z): 354 [MH]⁺, 3Cl

Intermediate 10

[4-Chloro-7-(2,4-dichlorophenyl)-2-methyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl]-acetaldehyde

A solution of intermediate 9 (30 mg) in CH₂Cl₂ (4 mL) was ozonized (5g.h⁻¹) at −78° C. for 5 min. When all the starting material haddisappeared (according to TLC in cHex/EtOAc 75/25), the reaction mixturewas first flushed with oxygen and then with nitrogen for 20 min. To thecooled reaction mixture was added (CH₃)₂S (25 μl, 4 eq) and thetemperature was allowed to warm up to r.t. The solution was stirred for18 hr at that temperature. The solvent was removed in vacuo and thecrude product was purified by flash chromatography (silica gel,cHex/EtOAc 3:1) to give the title compound (8 mg) as a colourless oil.

NMR (¹H, CDCl₃): δ 9.87 (s, 1H), 7.48 (t, 1H), 7.30 (m, 2H), 4.23 (t,1H), 3.90 (m, 1H), 3.60 (dd, 1H), 3.29 (dd, 1H), 2.90 (dd, 1H), 2.42 (s,3H).

MS (m/z): 356 [MH]⁺, 3Cl.

Intermediate 11

5-[1-(tert-Butyl-diphenyl-silanyloxymethyl)-but-3-enyl]-4,6-dichloro-2-methyl-pyrimidine

To a solution of intermediate 3 (152 mg) in anh. DMF (4 mL), at 0° C.,under N₂, was added DMAP (3.8 mg), imidazole (420 mg) and Ph₂tBuSiCl(0.32 mL). The reaction mixture was stirred at r.t. for 2 hr. To thissolution were added 5 mL of sat.aq. NH₄Cl and the mixture was extractedwith Et₂O (2×15 mL). The combined organic extracts were washed once withwater, once with brine and dried over Na₂SO₄. The solids were filtered,the solvent was evaporated and the crude yellow oil was purified byflash chromatography (silica gel, cHex/EtOAc 95:5) to give the titlecompound as a colourless oil (270 mg).

NMR (¹H, CDCl₃): δ 7.65 (dd, 2H), 7.56 (dd, 2H), 7.49-7.36 (m, 6H), 5.67(m, 1H), 5.03 (dd, 1H), 4.94 (dd, 1H), 4.17 (m, 1H), 4.00 (m, 2H), 2.70(s, 3H), 2.69 (m, 1H), 2.55 (m, 1H), 0.98 (s, 9H).

MS (m/z): 485 [MH]⁺, 2Cl.

Intermediate 12

{5-[1-(tert-Butyl-diphenyl-silanyloxymethyl)-but-3-enyl]-6-chloro-2-methyl-pyrimidin-4-yl}-(2,4-dichlorophenyl)-amine

To a solution of 2,4-dichloroaniline (80 mg) in anh. THF (1 mL), at 0°C., under N₂, was added NaH (80% in mineral oil, 31 mg) and left toreact at r.t. for 30 min. To this mixture cooled back at 0° C. was addeda solution of intermediate 11 (227 mg, 0.467 mmol) in anh. THF (2 mL).The reaction mixture was stirred at reflux for 5 hr. It was thenquenched with water (20 mL), and extracted with Et₂O (4×20 mL). Thecombined organic extracts were washed once with water, once with brineand dried over anh. Na₂SO₄. The solids were filtered, the solventevaporated and the crude orange oil was purified by flash chromatography(silica gel, cHex/EtOAc 95:5) to give the title compound as yellow oil(131.6 mg).

NMR (¹H, CDCl₃): δ 8.2-7.7 (broad d, 1H), 7.55 (d, 2H), 7.50 (d, 2H),7.40-7.20 (m, 9H), 5.70 (m, 1H), 5.07 (dd, 1H), 4.94 (dd, 1H), 4.06 (m,2H), 3.70 (m, 1H), 2.71 (m, 2H), 2.50 (m, 3H), 0.95 (s, 9H).

MS (m/z): 610 [MH]⁺, 3 Cl.

Intermediate 13

{5-[1-(tert-Butyl-diphenyl-silanyloxymethyl)-but-3-enyl]-6-chloro-2-methyl-pyrimidin-4-yl}-(2,4-dichlorophenyl)-carbamicacid tert-butyl ester

To a solution of intermediate 12 (128 mg) in anh. CH₂Cl₂ (2 mL), atr.t., under N₂, were added Boc₂O (61 mg) and DMAP (3 mg). The reactionmixture was stirred at r.t. for 16 hr. The complete conversion of thestarting material was obtained after 2 days by addition of fresh Boc₂O(58 mg+46 mg) and catalytic amounts of DMAP. The reaction mixture wasthen diluted with water and extracted with CH₂Cl₂ (2×5 mL). The combinedorganic extracts were washed once with water and dried over anh. Na₂SO₄.The solids were filtered, the solvent evaporated and the crude yellowoil was purified by flash chromatography (silica gel, cHex/EtOAc 9:1) togive the title compound as pale yellow oil (138 mg).

NMR (¹H, DMSO, 70° C.): δ 7.67 (d, 1H), 7.54-7.30 (m, 5H+5H), 7.19 (m,2H), 5.51 (m, 1H), 4.87 (d, 1H), 4.82 (d, 1H), 3.94 (m, 1H), 3.84 (bm,1H), 3.53 (m, 1H), 2.57 (s, 3H), 2.62 (m, 1H), 2.35 (m, 1H), 1.35 (s,9H), 0.90 (s, 9H).

IR (nujol, cm⁻¹): 1732.

MS (m/z): 710 [MH]⁺, 3 Cl, 722 [M+Na]⁺, 610 [MH−Boc+H]⁺.

Intermediate 14

{5-[1-(tert-Butyl-diphenyl-silanyloxymethyl)-3-hydroxy-propyl]-6-chloro-2-methyl-pyrimidin-4-yl}-(2,4-dichlorophenyl)-carbamicacid tert-butyl ester

A solution of intermediate 13 (108 mg) in 3 mL of CH₂Cl₂/CH₃OH (9:1) wascooled at −78° C. O₃ was bubbled in the solution for 30 min undermagnetic stirring. NaBH₄ (23.1 mg) was then added under N₂ atmosphere atlow temperature. The reaction mixture was stirred for 3 hr at r.t. Itwas then quenched with water and extracted with CH₂Cl₂ (2×5 mL). Thecombined organic extracts were washed once with sat.aq. NH₄Cl and driedover anh. Na₂SO₄. The solids were filtered, the solvent was evaporatedand the crude yellow oil was purified by flash chromatography (silicagel, cHex/EtOAc 9:1) to give the title compound as a colourless oil (59mg).

NMR (¹H, DMSO, 70° C.): δ 7.65 (d, 1H), 7.48-7.34 (m, 5H+5H), 7.28 (d,1H), 7.12 (bd, 1H), 5.51 (m, 1H), 4.18 (t, 1H), 4.02 (bt, 1H), 3.82 (bm,1H), 3.51 (m, 1H), 3.29 (bm, 2H), 2.55 (s, 3H), 2.05 (m, 1H), 1.84 (bm,1H), 1.35 (s, 9H), 0.89 (s, 9H).

IR (film, cm⁻¹): 1733.

MS (m/z): 714 [MH]⁺, 3 Cl, 736 [M+Na]⁺, 3 Cl, 678 [MH−HCl]⁺, 2 Cl, 614[MH−Boc+H]⁺.

Intermediate 15

Methanesulfonic acid3-{4-[tert-butoxycarbonyl-(2,4-dichlorophenyl-amino]-6-chloro-2-methyl-pyrimidin-5-yl}-4-(tert-butyl-diphenyl-silanyloxy)-butylester

To a solution of intermediate 14 (57 mg) in anh. CH₂Cl₂ (1 mL), wereadded Et₃N (55 μl) and MsCl (13 μl) at r.t., under N₂. The reactionmixture was stirred for 5 hr, diluted with water and extracted withCH₂Cl₂ (2×5 mL). The combined organic extracts were washed once withwater, once with brine, and dried over anh. Na₂SO₄. The solids werefiltered, the solvent evaporated to obtain the crude colourless titlecompound (60 mg).

NMR (¹H, DMSO, 70° C.): δ 7.65 (d, 1H), 7.50-7.34 (m, 5H+5H), 7.24 (bd,1H), 7.15 (bd, 1H), 4.20-4.00 (m, 3H), 3.80-3.60 (m, 2H), 3.02 (s, 3H),2.56 (s, 3H), 2.30-2.10 (m, 2H), 1.35 (s, 9H), 0.89 (s, 9H).

IR (nujol, cm⁻¹): 1725.

MS (m/z): 794 [MH]⁺, 3 Cl, 694 [MH−Boc+H]⁺.

Intermediate 16

Methanesulfonic acid4-(tert-butyl-diphenyl-silanyloxy)-3-[4-chloro-6-(2,4-dichlorophenyl-amino)-2-methyl-pyrimidin-5-yl]-butylester

To a solution of intermediate 15 (58 mg) in anh. CH₂Cl₂ (1 mL), at r.t.,under N₂, was added TFA (200 μl, 35 eq). The reaction mixture wasstirred for 16 hr, then evaporated under reduced pressure, dilutedseveral times with CH₂Cl₂ and evaporated again to obtain the crude titlecompound (64 mg) as a yellow oil.

MS (m/z): 694 [MH]⁺, 3 Cl.

Intermediate 17

5-(tert-Butyl-diphenyl-silanyloxymethyl)-4-chloro-8-(2,4-dichlorophenyl)-2-methyl-5,6,7,8-tetrahydro-pyrido[2,3-d]pyrimidine

To a solution of intermediate 16 (64 mg) in anh. THF (1 mL), at 0° C.,under N₂, was added Et₃N (100 μl). The reaction mixture was stirred for16 hr at r.t., then diluted with water and extracted with Et₂O (2×20mL). The combined organic extracts were washed once with water, oncewith brine and dried over anh. Na₂SO₄. The solids were filtered, thesolvent was evaporated and the crude oil was purified by flashchromatography (silica gel, cHex/EtOAc 95:5) to obtain the titlecompound as a colourless oil (26.4 mg).

NMR (¹H, CDCl₃): δ 7.74-6.98 (m, 5H+5H+1H+2H), 4.10-3.90, 3.76-3.55,3.48-3.28 (m, 5H), 2.58-2.38 (m, 1H), 2.24, 2.22 (s, 3H), 2.1-1.9 (m,1H), 1.07 (s, 9H).

MS (m/z): 598 [MH]⁺, 3 Cl.

Intermediate 18

[4-Chloro-8-(2,4-dichlorophenyl)-2-methyl-5,6,7,8-tetrahydro-pyrido[2,3-d]pyrimidine-5-yl]-methanol

To a solution of intermediate 17 (22 mg) in anh. DMF (2 mL), at r.t.,under N₂, was added Et₃N3HF (20 μl). The reaction mixture was stirredfor 4 hr at 40° C., then diluted with water and extracted with Et₂O(3×20 mL). The combined organic extracts were washed once with water,once with brine and dried over anh. Na₂SO₄. The solids were filtered,the solvent evaporated and the crude oil was purified by flashchromatography (silica gel, cHex/EtOAc 2:1) to give the title compoundas colourless oil (13 mg).

NMR (¹H, DMSO, 90° C.): δ 7.66 (bs, 1H), 7.50-7.42 (m, 2H), 4.66 (m,1H), 3.82 (bt, 1H), 3.68 (m, 1H), 3.66-3.36 (m, 2H), 3.20 (m, 1H), 2.33(m, 1H), 2.14 (s, 3H), 1.94 (m, 1H).

MS (m/z): 358 [MH]⁺, 3 Cl, 360.

Intermediate 19

Methanesulfonic acid4-chloro-8-(2,4-dichlorophenyl)-2-methyl-5,6,7,8-tetrahydro-pyrido[2,3-d]pyrimidine-5-ylmethylester

To a solution of intermediate 18 (13 mg) in anh. CH₂Cl₂ (1 mL), at 0°C., under N₂, were added Et₃N (20.0 μl) and MsCl (6.0 μl). The reactionmixture was stirred for 16 hr at r.t., then diluted with water andextracted with CH₂Cl₂ (3×10 mL). The combined organic extracts werewashed once with water, once with brine and dried over anh. Na₂SO₄. Thesolids were filtered and the solvent was evaporated to give the crudetitle compound (14.7 mg) as a colourless oil.

NMR (¹H, CDCl₃): δ 7.50 (dd, 1H), 7.40-7.15 (m, 2H), 4.50-4.15 (m, 2H),3.90-3.70 (m, 1H), 3.65-3.30 (m, 2H), 3.05 (s, 3H), 2.45-2.2 (m, 1H),2.25 (s, 3H), 2.2-2.0 (m, 1H).

MS (m/z): 438 [MH]⁺, 3 Cl.

Intermediate 20

5-Iodo-pentanoic acid methyl ester

To a solution of methyl 4-bromovalerate (14 g) in acetone (63 mL), NaI(11.5 g) was added and the mixture was refluxed for 2 hr. It was thencooled to r.t. and the precipitate was filtered. The filtrate wasevaporated and ether was added to the residue. The resulting suspensionwas filtered and the ethereal phase washed with 5% aq NaHSO₃ (3×100 mL)and with brine (1×100 mL) and dried over anh. Na₂SO₄. The solids werefiltered and the solvent evaporated to give the crude title compound asa yellow oil (15.85 g).

NMR (¹H, CDCl₃): δ 3.68 (s, 3H), 3.19 (t, 2H), 2.34 (t, 2H), 1.86 (m,2H), 1.74 (m, 2H).

MS (m/z): 242 [M]⁺, 211 [M−OMe]⁺, 115 [M−I]⁺.

Intermediate 21

2-(2,4-dichlorophenyl)-heptanedioic acid dimethyl ester

To a solution of methyl 2,4-dichlorophenylacetate (2 g) in anh. THF (27mL), at −78° C., under N₂, a 1M solution of LHMDS in THF (10.04 mL) wasadded dropwise and the mixture was stirred at −78° C. for 30 min. Neatintermediate 20 (2.87 g, 1.3 eq) was then added dropwise at −78° C. andthe dropping funnel was washed with anh. THF (2 mL). The cooling bathwas then removed and the mixture was stirred at r.t. for 3.5 hr. Thesolvents were evaporated under reduced pressure. The residue wasdissolved in ether, washed with water (3×30 mL) and brine (1×30 mL) anddried over anh. Na₂SO₄. The solids were filtered and the solventevaporated. The crude product was purified by flash chromatography(silica gel, cHex/EtOAc 9:1) to give the title compound as a pale yellowoil (2.7 g).

NMR (¹H, CDCl₃): δ 7.39 (d, 1H), 7.30 (d, 1H), 7.22 (dd, 1H), 4.10 (t,1H), 3.67 (s, 3H), 3.65 (s, 3H), 2.29 (t, 2H), 2.05 (m, 1H), 1.74 (m,1H), 1.64 (m, 2H), 1.40-1.20 (m, 2H).

IR (film, cm⁻¹): 1738.

MS (m/z): 332 [M]⁺, 300 [M−CH₃OH]⁺, 159.

Intermediate 22

3-(2,4-Dichlorophenyl)-2-hydroxy-cyclohex-1-enecarboxylic acid methylester

Sodium (0.7 g) was added portionwise under vigorous stirring, at 0° C.,under N₂, to anh. MeOH (26 mL). After consumption of metallic sodium,anh. toluene (100 mL) was added and a MeOH/toluene mixture (36 mL) wasdistilled off by means of a Dean-Stark apparatus. The mixture wasallowed to cool to r.t. before adding a solution of intermediate 21(2.52 g) in anh. toluene (1 mL). The mixture was refluxed for 3.5 hr andthen cooled to r.t. before acidifying with AcOH. The organic phase waswashed with water. The aqueous phase was extracted with EtOAc (2×20 mL)and the combined organic extracts were washed with water (2×20 mL),brine (2×20 mL) and dried over anh. Na₂SO₄. The solids were filtered andthe solvent evaporated. The crude product was purified by flashchromatography (silica gel, cHex/EtOAc 95:5) to obtain the titlecompound (colourless oil: 1.8 g)

NMR (¹H, CDCl₃): δ 12.19 (s, 1H), 7.40 (d, 1H), 7.19 (dd, 1H), 7.08 (d,1H), 4.07 (t, 1H), 3.81 (s, 3H), 2.35 (m, 2H), 2.01 (m, 1H), 1.73 (m,1H), 1.60 (m, 2H).

MS (m/z): 300 [M]⁺, 265, 233.

Intermediate 23

5-(2,4-Dichlorophenyl)-6-oxo-cyclohex-1-enecarboxylic acid methyl ester

Phenylselenenylchloride (2.44 g) was placed in a two-necked flask undernitrogen and dissolved in anh. CH₂Cl₂ (21 mL). The brown solution wascooled to 0° C. and anh. pyridine (0.9 mL) was added resulting in ayellow solution which was stirred at 0° C. for 30 min. A solution ofintermediate 22 (1.5 g) in anh. CH₂Cl₂ (12 mL) was added dropwise at 0°C. and the reaction mixture was stirred at r.t. for 4.5 hr. The reactionmixture was then transfered to a separatory funnel and washed with 1MHCl (2×10 mL) and with water (3×10 mL). The CH₂Cl₂ layer was thentransfered to a flask and cooled to 0° C. Aqueous H₂O₂ (30% w/w, 3 mL)was added and the mixture was stirred for 10 min at 0° C. followed byaddition of a second aliquot of H₂O₂ (3 mL). The reaction mixture turnedcolourless and a white solid formed. After 20 min at 0° C. the mixturewas washed with sat.aq. NaHCO₃ (2×10 mL) and brine (1×10 mL) and driedover anh. Na₂SO₄. The solids were filtered and the solvent evaporated togive the title compound (1.45 g) as a pale yellow oil, which becomessolid by cooling.

NMR (¹H, CDCl₃): δ 7.77 (m, 1H), 7.43 (d, 1H), 7.24 (dd, 1H), 7.11 (d,1H), 4.12 (dd, 1H), 3.83 (s, 3H), 2.70 (m, 2H), 2.40-2.20 (m, 2H).

IR (film, cm⁻¹): 1737, 1673.

MS (m/z): 298 [M]⁺, 263 [M−Cl]⁺, 126.

Intermediate 24

5-Allyl-8-(2,4-dichlorophenyl)-2-methyl-5,6,7,8-tetrahydroquinazolin-4-ol

To a solution of intermediate 23 (690 mg) in anh. CH₂Cl₂ (6.5 mL), at−78° C., TiCl₄ (0.255 mL) was added. The resulting brown solution wasstirred at −78° C. for 5 min, after which a solution ofallyltrimethylsilane (0.440 mL) in anh. CH₂Cl₂ (6.5 mL) was added. Afterstirring for 1.5 hr at −78° C., the reaction was quenched with water,diluted with CH₂Cl₂ and the mixture was allowed to warm to r.t. Theaqueous layer was extracted with CH₂Cl₂ and the organic phase was washedwith brine (1×10 mL) and dried over anh. Na₂SO₄. The solids werefiltered and the solvent evaporated to obtain the allylated compound(676 mg) as pale yellow oil and as a mixture of diastereoisomericenolesters and ketoesters.

Sodium (140 mg, 3 eq) was added portionwise to anh. MeOH (6 mL) underN₂. After consumption of metallic sodium, acetamidine hydrochloride (600mg) was added. After 10 min of stirring, the precipitated NaCl wasfiltered off and washed with anh. MeOH (2 mL). The solution of freeacetamidine was added to the crude allylated product (676 g) and themixture was stirred at r.t. for 18 hr. The solvent was evaporated andthe crude product was purified by flash chromatography (silica gel,CH₂Cl₂/MeOH 98:2→97:3) to give the title compound as a 3:1 mixture oftwo diastereoisomers (538 mg).

NMR (¹H, CDCl₃)(anti isomer): δ 11.82 (bs, 1H), 7.42 (d, 1H), 7.10 (dd,1H), 6.58 (d, 1H), 5.87 (m, 1H), 5.06 (m, 2H), 4.34 (d, 1H), 3.01 (m,1H), 2.68 (m, 1H), 2.37 (s, 3H), 2.20 (m, 1H), 2.07 (m, 1H), 1.80 (m,1H), 1.70 (m, 1H), 1.49 (m, 1H).

NMR (¹H, CDCl₃)(syn isomer): δ 11.70 (bs, 1H), 7.36 (d, 1H), 7.12 (dd,1H), 6.81 (d, 1H), 5.83 (m, 1H), 5.02 (m, 2H), 4.23 (bt, 1H), 2.98 (m,1H), 2.66 (m, 1H), 2.28 (s, 3H), 2.20 (m, 1H), 2.02-1.80 (m, 2H),1.62-1.47 (m, 2H).

MS (m/z): 348 [M]⁺, 307 [M−allyl]⁺.

Intermediate 25

Anti-5-Allyl-4-chloro-8-(2,4-dichlorophepyl)-2-methyl-5,6,7,8-tetrahydroquinazoline(isomer 1) andSyn-5-Allyl-4-chloro-8-(2,4-dichlorophepyl)-2-methyl-5,6,7,8-tetrahydroquinazoline(isomer 2)

Intermediate 24 (538 mg) was dissolved in POCl₃ (5 mL) and the mixturewas refluxed for 2 hr. The POCl₃ was evaporated, the residue wasdissolved in CH₂Cl₂ and treated with conc. NH₄OH. The two phases wereseparated and the aqueous layer was extracted with CH₂Cl₂ (3×10 mL). Thecombined organic extracts were washed with brine (2×10 mL) and driedover Na₂SO₄. The solids were filtered and the solvent evaporated. Thecrude product was purified by flash chromatography (silica gel,cHex/EtOAc 95:5)to give the title compound isomer 1 (262 mg) and thetitle compound isomer 2 (94 mg) as colourless oils.

isomer 1:NMR (¹H, CDCl₃): δ 7.44 (d, 1H), 7.06 (dd, 1H), 6.20 (d, 1H),5.86 (m, 1H), 5.14 (m, 2H), 4.63 (d, 1H), 3.16 (m, 1H), 2.60 (m, 1H),2.59 (s, 3H), 2.30 (m, 1H), 2.16 (m, 1H), 1.89 (m, 1H), 1.80 (m, 1H),1.64 (m, 1H).

MS (m/z): 367 [M+H]⁺.

isomer 2:NMR (¹H, CDCl₃): δ 7.36 (d, 1H), 7.15 (dd, 1H), 6.83 (bd, 1H),5.82 (m, 1H), 5.10-5.06 (m, 2H), 4.35 (m, 1H), 3.12 (m, 1H), 2.62 (m,1H), 2.48 (s, 3H), 2.25 (m, 1H), 2.22-2.00 (m, 2H), 1.90-1.78 (m, 2H).

MS (m/z): 367 [M+H]⁺.

Intermediate 26

[5-Allyl-7-(2,4-dichlorophenyl)-2-methyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl]-cyclopropylmethyl-amine

A solution of intermediate 9 (160 mg, 0.451 mmol) incyclopropylmethylamine (0.5 mL) was heated at 130° C. (screw cap vial)for 4 hr. The amine was then evaporated and the residue was purified byflash chromatography (silica gel, gradient: CH₂Cl₂/EtOAc 9:1 to 7:3) togive the title compound (162 mg, 0.416 mmol, 92%) as a colourless oil.

NMR (¹H, CDCl₃): δ 7.43 (d, 1H), 7.36 (d, 1H), 7.24 (dd, 1H), 5.86 (m,1H), 5.20-5.13 (m, 2H), 4.39 (bt, 1H), 3.88 (dd, 1H), 3.71 (dd, 1H),3.40-3.30 (m, 3H), 2.46 (m, 1H), 2.35 (m, 1H), 2.36 (s, 3H), 1.08 (m,1H), 0.60-0.27 (m, 4H).

MS (m/z): 389 [M+H]⁺ (2 Cl).

Intermediate 27

5-Cyclopropylmethyl-1-(2,4-dichlorophenyl)-7-methyl-1,2,2a,3,4,5-hexahydro-1,5,6,8-tetraaza-acenaphthylen-4-ol

To a solution of intermediate 26 (160 mg, 0.411 mmol) in a 8:1 mixtureof acetone and water (8 mL) was added N-methylmorpholine-N-oxide (100mg, 2 eq), followed by a 4% aqueous solution of OsO₄ (0.260 mL, 0.1 eq)and the reaction mixture was stirred at r.t. for 3.5 hr. The solutionwas then concentrated under reduced pressure, and sat.aq. Na₂SO₃ (50 mL)was added. The aqueous phase was extracted with EtOAc (3×10 mL) anddried over anh. Na₂SO₄. The solids were filtered and the solventevaporated. The crude diol was dissolved in a 1:1 mixture of THF andwater (8 mL) and NaIO₄ (132 mg, 1.5 eq) was added. The reaction mixturewas stirred at r.t. for 45 min. It was then diluted with water andextracted with EtOAc (3×10 mL). The combined organic extracts werewashed once with brine and dried over anh. Na₂SO₄. The solids werefiltered and the solvent evaporated. The crude product was purified byflash chromatography (silica gel, cHex/EtOAc 1:1). The title compoundwas obtained as a colourless oil (111 mg, 0.284 mmol, 69%).

NMR (¹H, DMSO-d₆): δ 7.68 (d, 1H), 7.44 (m, 2H), 5.92 (d, 1H), 5.17 (m,1H), 4.13 (t, 1H), 3.79 (m, 1H), 3.76 (dd, 1H), 3.50 (m, 1H), 3.15 (dd,1H), 2.24 (m, 1H), 2.21 (s, 3H), 1.43 (dt, 1H), 1.06 (m, 1H), 0.50-0.20(m, 4H).

MS (m/z): 391 [M+H]⁺ (2 Cl).

Intermediate 28

5-Cyclopropylmethyl-1-(2,4-dichlorophenyl)-4-methoxy-7-methyl-1,2,2a,3,4,5-hexahydro-1,5,6,8-tetraaza-acenaphthylene

A solution of PTSA (1.5 mg, 0.042 eq) in anh. MeOH (1.5 mL) was added tothe neat intermediate 27 (73 mg, 0.187 mmol) and the resulting solutionwas stirred at r.t. for 18 hr. The solvent was then evaporated and theresidue was dissolved in CH₂Cl₂ (10 mL). A solution prepared by dilutingsat.aq. NaHCO₃ with water (1:1, 10 mL) was then added and the aqueousphase was extracted with CH₂Cl₂ (2×10 mL). The combined organic extractswere washed with water (1×10 mL), sat.aq. NaCl (1×10 mL) and dried overanh. Na₂SO₄. The solids were filtered and the solvent evaporated. Thetitle compound was obtained as a yellow oil and was used in thesubsequent step without further purification (68 mg, 0.168 mmol, 90%).

NMR (¹H, acetone-d₆): δ 7.53 (d, 1H), 7.47 (d, 1), 7.35 (dd, 1H), 4.93(t, 1H), 4.23 (t, 1H), 4.05 (dd, 1H), 3.78 (dd, 1H), 3.51 (m, 1H), 3.39(s, 3H), 3.13 (dd, 1H), 2.53 (dddd, 1H), 2.25 (s, 3H), 1.40 (dt, 1H),1.09 (m, 1H), 0.50-0.20 (m, 4H).

MS (m/z): 405 [MH]⁺2 Cl).

Intermediate 29

Alternative preparation of intermediate 2:2-[4-Chloro-7-(2,4-dichlorophenyl)-2-methyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl]-ethanol

To a solution of intermediate 10 (93 mg, 0.261 mmol) in a 2:1 mixture ofanh. CH₂Cl₂/MeOH (3 mL), at 0° C., under N₂, was added NaBH₄ (20 mg, 2eq). The reaction mixture was stirred at r.t. for 1 hr. The reaction wasthen quenched with water (10 mL) and concentrated under reducedpressure. The aqueous phase was extracted with EtOAc (3×10 mL) and thecombined organic extracts were dried over anh. Na₂SO₄. The solids werefiltered and the solvent evaporated. The title compound was obtained asa white solid (80 mg, 0.223 mmol, 85%) and was used without furtherpurification in the subsequent step.

NMR (¹H, CDCl₃): δ 7.54 (d, 1H), 7.40-7.30 (m, 2H), 4.20 (t, 1H), 3.93(dd, 1H), 3.87 (m, 2H), 3.75 (m, 1H), 2.57 (s, 3H), 2.27 (m, 1H), 1.99(m, 1H).

MS (m/z): 358 [MH]⁺ (3Cl).

Intermediate 30

Methanesulfonic acid2-[4-chloro-7-(2,4-dichlorophenyl)-2-methyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl]-ethylester

To a solution of intermediate 29 (80 mg, 0.223 mmol) in anh. CH₂Cl₂ (2mL), at r.t., under N₂, was added triethylamine (155 μL, 5 eq) followedby mesyl chloride (35 μL, 2 eq). The reaction mixture was stirred atr.t. for 1 hr. It was then quenched with water (10 mL) and extractedwith CH₂Cl₂ (3×10 mL). The combined organic extracts were washed oncewith brine and dried over anh. Na₂SO₄. The solids were filtered and thesolvent evaporated. The crude compound was purified by flashchromatography (silica gel, cHex/EtOAc 1:1). The title compound wasobtained as a pale yellow oil (71 mg, 0.163 mmol, 73%).

NMR (¹H, CDCl₃): δ 7.48 (m, 1H), 7.32 (m, 2H), 4.38 (m, 2H), 4.09 (t,1H), 3.82 (dd, 1H), 3.66 (m, 1H), 3.00 (s, 3H), 2.46 (m, 1H), 2.42 (s,3H), 2.14 (m, 1H).

MS (m/z): 436 [MH]⁺ (3Cl).

Intermediate 31

{5-[1-(tert-Butyl-diphenyl-silanyloxymethyl)-but-3-enyl]-6-chloro-2-methyl-pyrimidin-4-yl}-(2,4-bis-trifluoromethyl-phenyl)-amine

To a solution of 2,4-bis(trifluoromethyl)aniline (2.11 g, 9.21 mmol) inanh. DMF (45 mL), at 0° C., under N₂, was added NaH 80%/oil (608 mg, 2.2eq). After 30 min the reaction mixture was warmed to r.t. After 30 min asolution of intermediate 11 (4.46 g, 9.21 mmol) in anh. DMF (30 mL) wasadded. The reaction mixture was left at r.t. for 15 min, then cooleddown at 0° C. and diluted with water. The aqueous phase was extractedwith EtOAc (3×50 mL) and the combined organic extracts were washed withwater (50 mL), brine (50 mL) and then dried over anh. Na₂SO₄. The solidswere filtered and the solvent evaporated. The crude product was purifiedby flash chromatography (silica gel, cHex/EtOAc 97:3) to give the titlecompound (4.546 g, 6.71 mmol, 73%) as a clear oil.

NMR (¹H, DMSO): δ 8.34 (s, 1H), 7.97 (s, 1H), 7.53 (d, 1H), 7.48 (d,1H), 7.54-7.31 (m, 10H), 5.7 (m, 1H), 4.97 (d, 1H), 4.90 (d, 1H), 4.11(m, 1H), 3.99 (m, 1H), 3.72 (m, 1H), 2.56 (m, 2H), 2.18 (s, 3H), 0.91(s, 9H).

MS (m/z): 678 [MH]⁺.

Intermediate 32

5-(tert-Butyl-diphenyl-silanyloxymethyl)-4-chloro-2-methyl-8-(2,4-bis-trifluoromethyl-phenyl)-5,6,7,8-tetrahydro-pyrido[2,3-d]pyrimidin-7-ol

To a solution of intermediate 31 (2 g, 2.95 mmol) in an 8:1 mixture ofacetone/H₂O (36 mL), at r.t., were added N-methyl-morpholine-N-oxide(716 mg, 2 eq) and OsO₄ 4%/H₂O (1.8 mL, 0.1 eq). After 3.5 h the solventwas evaporated and a saturated solution of Na₂SO₃ was added. The productwas extracted with EtOAc (2×20 mL) and the combined organic extractswere dried over anh. Na₂SO₄. The solids were filtered and the solventwas evaporated. The oil obtained was dissolved in a 9:1 mixture ofTHF/H₂O (45 mL) and NaIO₄ (947 mg, 1.5 eq) was added. The reactionmixture was stirred at r.t. for 18 hr. It was then diluted with waterand the product was extracted with EtOAc (3×20 mL). The combined organicextracts were washed with brine and dried over anh. Na₂SO₄. The solidswere filtered and the solvent was evaporated to give the title compound(1.932 g, 2.85 mmol, 96%), as a mixture of two diastereoisomers.

NMR (¹H, Acetone):

Isomer 1: δ 8.15 (m, 2H), 7.72 (m, 5H), 7.44 (m, 6H), 6.19 (d, 1H), 5.27(m, 1H), 4.41 (t, 1H), 4.08 (dd, 1H), 3.52 (m, 1H), 2.81 (m, 1H), 2.35(m, 1H), 2.15 (s, 3H), 1.07 (s, 9H).

Isomer 2: δ 8.15 (m, 2H), 7.72 (m, 5H), 7.44 (m, 6H), 5.8-5.4 (m, 2H),4-3.8 (m, 2H), 3.6-3.4 (m, 1H), 3-2.8 (m, 1H), 2.35 (m, 1H), 2.15 (s,3H), 1.07 (s, 9H).

MS (m/z): 680 [MH]⁺.

Intermediate 33

5-(tert-Butyl-diphenyl-silanyloxymethyl)-4-chloro-2-methyl-8-(2,4-bis-trifluoromethyl-phenyl-5,6,7,8-tetrahydro-pyrido[2,3-d]pyrimidine

To a solution of intermediate 32 (1.93 g, 2.84 mmol) in anh. CH₂Cl₂ (50mL), at −78° C., were added Et₃SiH (1.82 mL, 4 eq) and BF₃.Et₂O (1.58mL, 4.4 eq). The reaction mixture was stirred 1 hr at −78° C. and thenwas allowed to warm to r.t. and stirred for 18 hr. A saturated solutionof NaHCO₃ was then added and the product was extracted with CH₂Cl₂ (3×50mL). The combined organic extracts were dried over anh. Na₂SO₄, thesolids were filtered and the solvent evaporated. The crude product waspurified by flash chromatography (silica gel, cHex/EtOAc 95:5) to givethe title compound (0.607 g, 9.16 mmol, 32%) as a white solid.

NMR (¹H, CDCl₃): δ 7.98-7.94 (d, 1H), 7.88-7.80 (dd, 1H), 7.7-7.587.44-7.32 (m, 10H), 7.35-7.14 (d, 1H), 3.98-3.94 (dd, 1H), 3.73-3.55 (m,1H), 3.63-3.59 (m, 1H), 3.44-3.36 3.38-3.3 (2m, 2H), 2.55-2.4 (m, 1H),2.17-2.15 (s, 3H), 2.04-1.9 (m, 1H), 0.98 (s, 9H).

MS (m/z): 664[MH]⁺.

Intermediate 34

{4-Chloro-2-methyl-8-(2,4-bis-trifluoromethyl-phenyl)-5,6,7,8-tetrahydro-pyrido[2,3-d]pyrimidin-5-yl}-methanol

To a solution of intermediate 33 (600 mg, 0.91 mmol) in anh. DMF (15mL), at r.t., under N₂, was added Et₃N.3HF (1.25 mL, 8.4 eq) and thereaction mixture was heated at 40° C. for 6.5 h. It was then cooled downto r.t. and diluted with water. The product was extracted with Et₂O(3×20 mL). The combined organic extracts were washed with brine anddried over anh. Na₂SO₄. The solids were filtered and the solventevaporated. The crude product was purified by flash chromatography(silica gel, cHex/EtOAc 6:4) to give the title compound (337 mg, 0.8mmol, 88%) as a clear oil.

NMR (¹H, DMSO): δ 8.26-8.12 (m, 2H), 7.9-7.8 (d, 1H), 5.08-4.98 (t, 1H),3.9-3.6 (2H), 3.7-3.3 (2H), 3.24-3.10 (1H), 2.3 (m, 1H), 2.09 (s, 3H),2.0-1.8 (m, 1H).

MS (m/z): 426[MH]⁺.

Intermediate 35

Methanesulfonic acid4-chloro-2-methyl-8-(2,4-bis-trifluoromethyl-phenyl)-5,6,7,8-tetrahydro-pyrido[2,3-d]pyrimidin-5-ylmethylester

To a solution of intermediate 34 (200 mg, 0.47 mmol), in anh. CH₂Cl₂ (10mL), under N₂, at 0° C., were added Et₃N (0.26 mL, 4 eq) and MsCl (73μl, 2 eq). The reaction mixture was warmed to r.t. and stirred for 18hr. It was then diluted with water and the product was extracted withCH₂Cl₂ (3×20 mL). The combined organic extracts were washed with brineand dried over anh. Na₂SO₄. The solids were filtered, the solventevaporated and the crude product was purified by flash chromatography(silica gel, cHex/EtOAc 6:4) to give the title compound (203 mg, 0.4mmol, 86%) as a clear oil.

NMR (¹H,DMSO): δ 8.3 8.14 (m, 2H), 7.95-7.8 (d+d, 1H), 4.56-4.20 (2H),3.9-3.4 (m, 3H), 3.25 (s, 3H), 2.11 (s, 3H), 2.2-1.9 (m, 2H).

MS (m/z): 504[MH]⁺.

Intermediate 36

{4-Chloro-2-methyl-7-(2,4-bis-trifluoromethyl-phenyl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-acetaldehyde

To a solution of intermediate 31 (0.6 g, 0.886 mmol) in anh. DMF (15mL), at r.t., under N₂ was added Et₃N.3HF (1.22 mL, 8.4 eq). Thereaction mixture was stirred at r.t. for 18 hr. The reaction mixture wasdiluted with water and the product was extracted with Et₂O (3×20 mL).The combined organic extracts were washed with brine and dried over anh.Na₂SO₄. The solids were filtered and the solvent evaporated. The crudeproduct was purified by flash chromatography (silica gel, cHex/EtOAc8:2) to give an alcohol intermediate (346 mg, 89%) which was dissolvedinto anh. CH₂Cl₂ (15 mL) and cooled down to 0° C. Et₃N (0.44 mL, 4 eq)and MsCl (0.122 mL, 2 eq) were added, and the reaction mixture waswarmed to r.t. and stirred for 18 hr. The reaction mixture was dilutedwith water and the product was extracted with CH₂Cl₂ (3×20 mL). Thecombined organic extracts were dried over anh. Na₂SO₄, the solids werefiltered and the solvent evaporated. The crude product was purified byflash chromatography (silica gel, cHex/EtOAc 8:2) to give a cyclicpyrrolidine intermediate (276 mg, 83%). This intermediate was dissolvedin an 8:1 mixture of acetone/H₂O (18 mL) and N-methyl-morpholine-N-oxide(230 mg, 2 eq) and OsO₄ (403 μl, 0.1 eq) were added. The reactionmixture was stirred at r.t. for 6 h. The solvent was evaporated and asaturated solution of Na₂SO₃ was added. The product was extracted withEtOAc (3×20 mL) and the combined organic extracts were dried over anh.Na₂SO₄. The solids were filtered and the solvent evaporated. The crudeproduct was dissolved into a 9:1 mixture of THF/H₂O (15 mL) and NaIO₄(210 mg, 1.5 eq) was added. The reaction mixture was stirred at r.t. for18 hr, then it was diluted with water and the product was extracted withEtOAc (3×20 mL). The combined organic extracts were washed with brineand dried over anh. Na₂SO₄. The solids were filtered and the solventevaporated to give the title compound (250 mg, 0.59 mmol, 90%) as aclear oil.

NMR (¹H, CDCl₃): δ 9.86 (s, 1H), 8.05 (s, 1H), 7.93 (d, 1H), 7.5 (d,1H), 4.24 (m, 1H), 3.93 (m, 1H), 3.65 (dd, 1H), 3.25 (dd, 1H), 2.93 (dd,1H), 2.4 (s, 3H).

MS (m/z): 424[MH]⁺.

Intermediate 37

Methanesulfonic acid2-{4-chloro-2-methyl-7-(2,4-bis-trifluoromethyl-phenyl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-ethylester

To a solution of intermediate 36 (250 mg, 0.59 mmol) in a 9:1 mixture ofCH₂Cl₂/MeOH (15 mL), at 0° C., under N₂, was added NaBH₄ (44 mg, 2 eq).The reaction mixture was stirred for 30 min at 0° C. Conc. HCl was addeduntil pH=7 was reached. The reaction mixture was then diluted with waterand the product was extracted with CH₂Cl₂ (3×20 mL). The combinedorganic extracts were washed with brine and dried over anh. Na₂SO₄. Thesolids were filtered and the solvent evaporated to give a white solid(alcohol intermediate, 231 mg, 0.54 mmol, 93%) which was dissolved inanh. CH₂Cl₂ (15 mL). The reaction mixture was cooled at 0° C., then Et₃N(302 μl, 4 eq) and MsCl (85 μl, 2 eq) were added. The reaction mixturewas stirred at r.t. for 18 hr, then it was diluted with water and theproduct was extracted with CH₂Cl₂ (3×20 mL). The combined organicextracts were dried over anh. Na₂SO₄, the solids were filtered and thesolvent evaporated. The crude product was purified by flashchromatography (silica gel, cHex/EtOAc 6:4) to give the title compound(252 mg, 0.50 mmol, 93%) as a clear oil.

NMR (¹H, CDCl₃): δ 8.05 (bs, 1H), 7.94 (bd, 1H), 7.53 (bd, 1H), 4.42 (m,2H), 4.07 (t, 1H), 3.83 (dd, 1H), 3.71 (m, 1H), 3.04 (s, 3H), 2.46 (m,1H), 2.43 (s, 3H), 2.13 (m, 1H).

MS (m/z): 504[MH]⁺.

Intermediates 38 and 39

(S)-2-Acetoxy-propionic acid4-chloro-2-methyl-8-(2,4-bis-trifluoromethyl-phenyl)-5,6,7,8-tetrahydro-pyrido[2,3-d]pyrimidin-5(S)-ylmethylester and (S)-2-Acetoxy-propionic acid4-chloro-2-methyl-8-(2,4-bis-trifluoromethyl-phenyl)-5,6,7,8-tetrahydro-pyrido[2,3-d]pyrimidin-5(R)-ylmethylester

To a solution of intermediate 34 (320 mg, 0.753 mmol) in CH₂Cl₂ (7 mL)at 0° C., under N₂, were added DMAP (230 mg, 2.5 eq), Et₃N (0.73 mL, 7eq) and (S)-2-acetoxypropionyl chloride (0.61 mL, 6.4 eq). The reactionmixture was stirred at 0° C. for 30 min, warmed to r.t and diluted witha saturated solution of NaHCO₃. The product was extracted with CH₂Cl₂(3×30 mL) and the combined organic extracts were dried over anh. Na₂SO₄.The solids were filtered and the solvent was evaporated. The crudeproduct was purified by flash chromatography (silica gel, cHex/EtOAc8:2). The two diastereoisomers were separated by preparative chiralhplc: intermediate 38 (97 mg, 0.18 mmol, d.e.=97%) and intermediate 39(89.7 mg, 0.17 mmol, d.e.>99%) were obtained as white solids.

NMR (¹H, Acetone):

Intermediate 38: δ 8.22-8.13 (m, 2H), 7.96-7.8 (d+d, 1H), 5.06 (, 11H),4.56-4.34 (m, 2H), 4.07-3.54 (m, 3H), 2.34-2.05 (m, 2H), 2.7 (s, 3H),2.06 (s, 3H), 1.48 (d+d, 3H).

Intermediate 39: δ 8.22-8.14 (m, 2H), 7.96-7.81 (d+d, 1H), 5.06 (m, 1H),4.5-4.3 (m, 2H), 4.1-3.54 (m, 3H), 2.7 (s, 3H), 2.3-2.0 (m, 2H), 2.13(s, 3H), 1.47 (d, 3H).

MS (m/z): 540[MH]⁺.

HPLC: Preparative: Pre-column/Guard column: Filter Rhodyne Column type:Daicel CHIRALPAK AD Column length [cm]:  25 Internal diameter [mm]:  2Injection volume [μl]: 500 Mobile phase: n-hexane-IPA 90/10 v/v Flowrate [mL/min]:  6.5 Detector type: DAD Wavelength [nm]: 225, 292Intermediate 38: 21.8, r.t. (min) Intermediate 39: 26.5, r.t. (min)Analytical: Pre-column/Guard column: Filter Rhodyne Column type:CHIRALPAK AD Column length [cm]:  25 Internal diameter [mm]:  4.6Particle size [μm]:  5 Column temperature [{circumflex over ( )}C]: r.t.Autosampler temperature [{circumflex over ( )}C] r.t. Injection volume[μl]:  20 Mobile phase: n-hexane/isopropylalcohol 90/10 v/v Flow rate[mL/min]:  1.0 Detector type: DAD Wavelength [nm]: 225 Intermediate 38:6.88, r.t. (min) Pre-column/Guard column: Filter Rhodyne Column type:CHIRALPAK AD Column length [cm]:  25 Internal diameter [mm]:  4.6 Columntemperature [° C.]: r.t. Autosampler temperature [° C.] r.t. Mobilephase: n-hexane/2-Propanol 90/10 v/v Flow rate [mL/min]:  1.0 Detectortype: DAD Wavelength [nm]: 220-350 Intermediate 39: 8.29, r.t. (min)Intermediate 40

{4-Chloro-2-methyl-8-(2,4-bis-trifluoromethyl-phenyl)-5,6,7,8-tetrahydro-pyrido[2,3-d]pyrimidin-5(S)-yl}-methanol

To a solution of intermediate 38 (90 mg, 0.167 mmol) in a 4:1 mixture ofTHF/H₂O (5 mL), at 0° C., was added LiOH (14 mg, 2 eq) and the reactionmixture was stirred for 50 min. It was then diluted with water and theproduct was extracted with Et₂O (2×10 mL) and with EtOAc (1×10 mL). Thecombined organic extracts were dried over anh. Na₂SO₄. The solids werefiltered, the solvent was evaporated and the crude product was purifiedby flash chromatography (silica gel, cHex/AcOEt 6:4) to give the titlecompound (65 mg, 0.15 mmol, 92%, e.e.=97%) as a clear oil.

NMR (¹H, DMSO): δ 8.3-8.1 (m, 2H), 7.88-7.81 (d+d, 1H), 5.00 (broad,1H), 3.9-3.6 (m, 2H), 3.7-3.3 (m, 2H), 3.2-3.1 (m, 1H), 2.3 (m, 1H),2.09 (s, 3H), 2.00-1.8 (m, 1H).

MS (m/z): 426[MH]⁺.

HPLC: Analytical Pre-column/Guard column: Filter Rhodyne Column type:Daicel CHIRALPAK AD Column length [cm]:  25 Internal diameter [mm]: 0.46 Column temperature [{circumflex over ( )}C]: r.t. Autosamplertemperature [{circumflex over ( )}C] r.t. Injection volume [μl]:  20Mobile phase: n-hexane/IPA/EtOH Step 1: Time-Reserv.A-ReservB:95/3.5/1.5 Flow rate [mL/min]:  1.0 Detector type: DAD Wavelength [nm]:225 Intermediate 40: 10.28, r.t. (min)Intermediate 41

Methanesulfonic acid4-chloro-2-methyl-8-(2,4-bis-trifluoromethyl-phenyl)-5,6,7,8-tetrahydro-pyrido[2,3-d]pyrimidin-5(S)-ylmethylester

To a solution of intermediate 40 (62 mg, 0.145 mmol) in anh. CH₂Cl₂ (5mL), at 0° C., under N₂, were added Et₃N (80 μl, 4 eq) and MsCl (23 μl,2 eq). The reaction mixture was brought to r.t., stirred for 1 h. andthen diluted with water. The product was extracted with CH₂Cl₂ (3×20 mL)and the combined organic extracts were washed with brine and dried overanh. Na₂SO₄. The solids were filtered and the solvent evaporated. Thecrude product was purified by flash chromatography (silica gel,cHex/EtOAc 6:4) to give the title compound (67 mg, 0.13 mmol, 92%,e.e.=95%) as a clear oil.

NMR (¹H, DMSO): δ 8.3-8.14 (m, 2H), 7.94-7.83 (d, 1H), 4.55-4.20 (2H),3.94-3.4 (m, 3H), 3.25 (s, 3H), 2.11 (s, 3H), 2.25-1.94 (m, 2H).

MS (m/z): 504[MH]⁺.

HPLC: Analytical Pre-column/Guard column: Filter Rhodyne Column type:CHIRALPAK AD Column length [cm]:  25 Internal diameter [mm]:  4.6Particle size [μm]:  5 Column temperature [{circumflex over ( )}C]: r.t.Autosampler temperature [{circumflex over ( )}C] r.t. Injection volume[μl]:  20 Mobile phase: n-hexane/EtOH/IPA 73.5/1.5/25 v/v Flow rate[mL/min]:  1.0 Detector type: DAD Wavelength [nm]: 225 Intermediate 41:6.52, r.t. (min)Intermediate 42

{4-Chloro-2-methyl-8-(2,4-bis-trifluoromethyl-phenyl)-5,6,7,8-tetrahydro-pyrido[2,3-d]pyrimidin-5(R)-yl}-methanol

To a solution of intermediate 39 (83 mg, 0.154 mmol) in a 4:1 mixture ofTHF/H₂O (5 mL), at 0° C., was added LiOH (14 mg, 2 eq) and the reactionmixture was stirred for 20 min. It was then diluted with water and theproduct was extracted with Et₂O (2×10 mL) and with EtOAc (1×10 mL), andthe combined organic extracts were dried over anh. Na₂SO₄. The solidswere filtered, the solvent was evaporated and the crude product waspurified by flash chromatography (silica gel, cHex/EtOAc 7:3) to givethe title compound (61 mg, 0.14 mmol, 93%, e.e.>99%) as a clear oil.

NMR (¹H, DMSO): δ 8.26-8.12 (m, 2H), 7.9-7.8 (d, 1H), 5.08-4.98 (t, 1H),3.9-3.6 (m, 2H), 3.7-3.3 (m, 2H), 3.24-3.1 (m, 1H), 2.3 (m, 1H), 2.09(s, 3H), 2.00-1.8 (m, 1H).

MS (m/z): 426[MH]⁺.

HPLC: Analytical Pre-column/Guard column: Filter Rhodyne Column type:CHIRALPAK AD Column length [cm]:  15 Internal diameter [mm]:  4.6Injection volume [μl]  10 Mobile phase: n-hexane/Ethanol/IPA Step 1:Time-Reserv.A-Reserv.B: 95/1.5/3.5 v/v Flow rate [mL/min]:  1.0 Detectortype: DAD Wavelength [nm]: 225 Intermediate 42: 9.417, r.t. (min)Intermediate 43

Methanesulfonic acid4-chloro-2-methyl-8-(2,4-bis-trifluoromethyl-phenyl)-5,6,7,8-tetrahydro-pyrido[2,3-d]pyrimidin-5(R)-ylmethylester

To a solution of intermediate 42 (58 mg, 0.136 mmol) in anh CH₂Cl₂ (5mL), at 0° C., under N₂, were added Et₃N (76 μl, 4 eq) and MsCl (21 μl,2 eq). The reaction mixture was brought to r.t., stirred for 1 h. andthen diluted with water. The product was extracted with CH₂Cl₂ (3×20 mL)and the combined organic extracts were washed with brine and dried overanh. Na₂SO₄. The solids were filtered, the solvent evaporated and thecrude product was purified by flash chromatography (silica gel,cHex/EtOAc 7:3) to give the title compound (57.6 mg, 0.11 mmol, 85%,e.e.>99%) as a clear oil.

NMR (¹H, DMSO): δ 8.3-8.14 (m, 2H), 7.95-7.8 (d, 1H), 4.56-4.20 (2H),3.9-3.4 (m, 3H), 3.25 (s, 3H), 2.11 (s, 3H), 2.2-1.9 (m, 2H).

MS (m/z): 504[MH]⁺.

HPLC: Analytical Pre-column/Guard column: Filter Rhodyne Column type:CHIRALPAK AD Column length [cm]:  25 Internal diameter [mm]:  4.6Particle size [μm]:  3 Injection volume [μl]:  10 Mobile phase:n-hexane/Ethanol/IPA Step 1: Time-Reserv.A-Reserv.B: 75/1.5/23.5 v/vFlow rate [mL/min]:  1.0 Detector type DAD Wavelength [nm]: 225Intermediate 43: 4.703, r.t. (min)Intermediate 44

3-(2,4-Dichloro-phenyl)-2-hydroxy-6-nitromethyl-cyclohex-1-enecarboxylicacid methyl ester

To a solution of intermediate 23 (26 mg, 0.087 mmol) in an anh. mixtureof Et₂O/THF (0.5 mL/0.1 mL) was added nitromethane (0.005 mL, 1.1 eq)and Amberlyst A21 (weekly basic resin: 260 mg). The solvent was slowlyevaporated at r.t. without agitation. After 2.5 hr, the dry resin wasdiluted with Et₂O and decanted. It was rinsed further with Et₂O (7×) andthe combined organic fractions were evaporated. The crude product waspurified by flash chromatography (silica gel, cHex/EtOAc, 9:1) to givethe title compound (25 mg, 80%) as a clear oil.

NMR (¹H, CDCl₃): δ 12.72 (s, 1H), 7.41 (d, 1H), 7.24 (dd, 1H), 7.03 (d,1H), 4.64 (dd, 1H), 4.50 (t, 1H), 4.07 (bm, 1H), 3.87 (s, 3H), 3.58 (m,1H), 2.08 (bm, 1H), 1.85 (bm, 3H).

MS (m/z): 359 [MH]⁺ (2 Cl).

Intermediate 45

8-(2,4-Dichloro-phenyl)-2-methyl-5-nitromethyl-5,6,7,8-tetrahydro-quinazolin-4-ol

Sodium (21 mg, 3.1 eq) was added portionwise to anh. MeOH (1.5 mL) underN₂. After consumption of metallic sodium, acetamidine hydrochloride (96mg, 3.3 eq) was added. After 10 min of stirring, the precipitated NaClwas filtered off and washed with anh. MeOH (2 mL). The solution of freeacetamidine was added to intermediate 44 (106 mg, 0.294 mmol) and themixture was stirred at r.t. for 18 hr. The solvent was evaporated andthe crude product was purified by flash chromatography (silica gel,EtOAc/cHex 8:2) to give the title compound as a clear oil (81 mg, 75%).

MS (m/z): 368 [MH]⁺ (2 Cl).

Intermediate 46

4-Chloro-8-(2,4-dichloro-phenyl)-2-methyl-5-nitromethyl-5,6,7,8-tetrahydro-quinazoline

A solution of intermediate 45 (73 mg, 0.198 mg) in POCl₃ (2 mL) washeated at reflux for 2.5 hr. POCl₃ was evaporated and the residue wastaken up in CH₂Cl₂. The organic phase was washed with conc. NH₄OH, thephases were separated and the aqueous layer was extracted with CH₂Cl₂(3×10 mL). The combined organic extracts were washed with sat.aq. NaCland dried over anh. Na₂SO₄. The solids were filtered and the solvent wasevaporated. The crude title compound (68 mg, 89%) was used as such inthe next step.

MS (m/z): 386 [MH]⁺ (3 Cl).

Intermediate 47

4-Chloro-8-(2,4-dichloro-phenyl)-2-methyl-5,6,7,8-tetrahydro-quinazoline-5-carbaldehyde

To a stirred solution of intermediate 46 (64 mg, 0.166 mmol) in anh.MeOH (1 mL), at −10° C., under N₂, was added methanolic KOH (0.1M, 2.3mL) dropwise. After stirring at −10° C. for 15 min, a solution of KMnO₄(18 mg, 0.7 eq) and MgSO₄ (20 mg, 1 eq) in H₂O (2.5 mL) was addeddropwise (reaction temperature kept below 0° C.). The reaction mixturewas stirred at 0° C. for 24 hr. It was then filtered on Celite, and theCelite cake washed with CH₂Cl₂. The solvent was evaporated and theaqueous phase extracted with CH₂Cl₂ (3×10 mL). The combined organicextracts were dried over anh. Na₂SO₄, the solids were filtered and thesolvent evaporated. The crude oil obtained was purified by flashchromatography (silica gel, cHex/EtOAC 9:1→8:2). The title compound wasobtained as a 65:35 mixture of diastereomers (27 mg, 46%, clear oil).

MS (m/z): 355 [MH]⁺ (3 Cl).

Example 1 Synthesis of Representative Compounds of Structure (I-1)5-(2,4-Dichlorophenyl)-1-(1-ethylpropyl)-7-methyl-1,2,2a,3,4,5-hexahydro-1,5,6,8-tetraaza-acenaphthylene(I-1-1)

A solution of intermediate 19 (14 mg) in pure 3-pentylamine (60 μl) wasstirred at 120° C. for 8 hr. The reaction mixture was then diluted withwater and extracted with Et₂O (3×10 mL). The combined organic extractswere washed once with water, once with brine and dried over anh. Na₂SO₄.The solids were filtered, the solvent evaporated and the crude paleyellow oil was purified by flash chromatography (silica gel, cHex/EtOAc8:2) to give the title compound as a pale yellow oil (5.9 mg).

5-(2,4-Dichlorophenyl)-1-(2-ethyl-butyl)-7-methyl-1,2,2a,3,4,5,5a,8b-octahydro-1,5,6,8-tetraaza-acenaphthylene(I-1-2)

A solution of intermediate 19 (10.0 mg) in pure 2-ethyl-n-butylamine(100 μl) was stirred in a sealed vial at 120° C. for 7 hr. The reactionmixture was then cooled down to r.t. and directly purified by flashchromatography (silica gel, Toluene/EtOAc 95:5) to give the titlecompound as pale yellow oil (1.9 mg).

5-(2,4-Dichlorophenyl)-1-(2-methoxy-1-methoxymethyl-ethyl)-7-methyl-1,2,2a,3,4,5,5a,8b-octahydro-1,5,6,8-tetraazaacenaphthylene(I-1-3)

A solution of intermediate 19 (16.5 mg) in pure2-methoxy-1-(methoxymethyl)ethylamine (52.6 mg) was stirred at 150° C.(screw cap vial) for 4 hr. The reaction mixture was then cooled down tor.t. and directly purified by flash chromatography (silica gel,Toluene/EtOAc 6:4) to obtain the title compound as a pale yellow oil(4.2 mg).

7-Methyl-1-(1-propylbutyl)-5-(2,4-bis-trifluoromethyl-phenyl)-1,2,2a,3,4,5-hexahydro-1,5,6,8-tetraaza-acenaphthylen(I-1-4).

Intermediate 35 (135 mg, 0.27 mmol) and 4-aminoheptane (0.5 mL, 12 eq)were heated at 130° C. (screw cap vial) for 3 hr. The reaction mixturewas then cooled down to r.t. and diluted with CH₂Cl₂. The solvent wasevaporated and the crude product was purified by flash chromatography(sililca gel, cHex/EtOAc 9:1) to give the title compound (29.4 mg, 0.06mmol, 23%) as a yellow solid.

Enantiomeric Resolution

First Enantiomer

7-Methyl-1-(1-propylbutyl)-5-(2,4-bis-trifluoromethyl-phenyl)-1,2,2a(S),3,4,5-hexahydro-1,5,6,8-tetraaza-acenaphthylene

Intermediate 41 (60 mg, 0.119 mmol) and 4-aminoheptane (178 μl, 10 eq)were heated at 130° C. (screw cap vial) for 3 h. The reaction mixturewas diluted with CH₂Cl₂ and the solvent was evaporated. The crudeproduct was purified by flash chromatography (silica gel, cHex/EtOAc95:5) to give the title compound (19.4 mg, 0.04 mmol, 33%, e.e.=95%) asa clear oil.

HPLC: Analytical Column type: CHIRALPAK OD Column length [cm]:  25Internal diameter [mm]:  4.6 Column temperature [{circumflex over( )}C]:  35 Injection volume [μl]:  10 Mobile phase: CO₂/EtOH (0.15%Ipa) 85/15 Flow rate [mL/min]:  2.5 Detector type: UV Wavelength [nm]:225 Column pressure [bar]: 150 Title compound: 2.55, r.t. (min)

¹H-NMR and MS data are the same as reported in the following Table 1 forcompound I-1-4

Second Enantiomer

7-Methyl-1-(1-propylbutyl)-5-(2,4-bis-trifluoromethyl-phenyl)-1,2,2a(R),3,4,5-hexahydro-1,5,6,8-tetraaza-acenaphthylene

Intermediate 43 (55 mg, 0.109 mmol) and 4-aminoheptane (163 μl, 10 eq)were heated at 130° C. (screw cap vial) for 3 h. The reaction mixturewas diluted with CH₂Cl₂ and the solvent was evaporated. The crudeproduct was purified by flash chromatography (silica gel, cHex/EtOAc95:5) to give the title compound (25.7 mg, 0.053 mmol, 49%, e.e.>99%) asa clear oil.

HPLC: Analitical Column type: CHIRALPAK OD Column length [cm]:  25Internal diameter [mm]:  4.6 Column temperature [{circumflex over( )}C]:  35 Injection volume [μl]:  10 Mobile phase: CO₂/EtOH (0.15%Ipa) 85/15 Flow rate [mL/min]:  2.5 Detector type: UV Wavelength [nm]:225 Column pressure [bar]: 150 Title compound: 2.12, r.t. (min)

¹H-NMR and MS data are the same as reported in the following Table 1 forcompound I-1-4

5-(2,4-Dichlorophenyl)-7-methyl-1-(1-propylbutyl)-1,2,2a,3,4,5-hexahydro-1,5,6,8-tetraaza-acenaphthylene(I-1-5)

A solution intermediate 19 (20 mg, 0.046 mmol) in 4-aminoheptane (100μL) was heated at 130° C. (screw cap vial) for 18 hr. The amine wasevaporated and the residue was directly purified by flash chromatography(silica gel, toluene/EtOAc, 9:1→8:2) to give the title compound as aclear oil (7 mg, 0.017 mmol, 36%).

Enantiomeric Resolution

First Enantiomer

5-(2,4-Dichlorophenyl)-7-methyl-1-(1-propylbutyl)-1,2,2a-(S),3,4,5,5a,8b-octahydro-1,5,6,8-tetraaza-acenaphthyl

Intermediate 47 (120 mg, 0.276 mmol) and 4-aminoheptane (0.412 mL, 10eq) was stirred at 130° C. (screw cap vial) for 18 hr. Then it wasdiluted with CH₂Cl₂ (5 mL) and the solvent was evaporated. The resultingcrude product was purified by flash chromatography (silica gel,cHex/EtOAc 9.5:0.5) to afford the title compound (62 mg, 53%, ee %>99%)as a clear oil.

HPLC: Analytical: Pre-column/Guard column: Rheodyne filter Column type:CHIRALPAK AD Column lenght (cm): 25 Internal diameter (mm):  4.6Particle size (μm):  5 Column temperature (° C.): r.t. Autosamplertemperature: (° C.): r.t. Injection volume (μL): 20 Mobile phase:n-Hexane/tert-butanol 90/10 a/a Flow rate (mL/min):  1 Detector type:DAD Wavelenght (nm): 220-350 Title compound: 10.2 rt (min)

¹H-NMR and MS data are the same as reported in the following Table 1 forcompound I-1-5.

Second Enantiomer

5-(2,4-Dichlorophenyl)-7-methyl-1-(1-propylbutyl)-1,2,2a-(R),3,4,5,5a,8b-octahydro-1,5,6,8-tetraaza-acenaphthyl

Intermediate 49 (130 mg, 0.298 mmol) and 4-aminoheptane (0.342 mL, 10eq) were stirred at 130° C. (screw cap vial) for 18 hr. Then it wasdiluted with CH₂Cl₂ (5 mL) and the solvent was evaporated. The resultingcrude product was purified by flash chromatography (silica gel,cHex/EtOAc 9.5:0.5) to afford the title compound (74 mg, 59%, ee %=90%)as a clear oil.

HPLC: Analytical: Pre-column/Guard column: Rheodyne filter Column type:CHIRALPAK AD Column lenght (cm): 25 Internal diameter (mm):  4.6Particle size (μm):  5 Column temperature (° C.): r.t. Autosamplertemperature: (° C.): r.t. Injection volume (μL): 20 Mobile phase:n-Hexane/tert-butanol 90/10 a/a Flow rate (mL/min):  1 Detector type:DAD Wavelenght (nm): 220-350 Title compound: 7.5, rt (min), 90%.

¹H-NMR and MS data are the same as reported in the following Table 1 forcompound I-1-5.

All the analytical data are set forth in the following Table 1.

TABLE 1 (I-1)

Cpd. No. R R₁ R₂— R₃— Analytical Data 1-1-1 2,4-dichloro-phenyl CH₃

H NMR (¹H, CDCl₃, 55° C.):δ 7.46(d, 1H), 7.35-7.25(m, 2H), 3.86(m, 1H),3.69(m, 1H), 3.63(bm, 2H),3.42(m, 1H), 3.23(m, 1H), 2.27(s, 3H),2.24(m,1H), 1.77(m, 1H), 1.70-1.40(m,4H), 1.00(t, 3H), 0.82(t, 3H).MS (m/z):391 [MH]⁺, 2 Cl. 1-1-2 2,4-dichloro-phenyl CH₃

H NMR (¹H, CDCl₃):δ 7.46(s, 1H), 7.26(m, 2H), 3.86(m,1H), 3.60(m,2H+1H), 3.40(m, 1H), 3.06(m, 1H), 2.70(dd, 1H), 2.35-2.20(m,2H), 2.29(s,3H), 1.60(m, 1H), 1.40-1.20(m, 4H), 0.94(t, 6H).MS (m/z): 405 [MH]⁺.1-1-3 2,4-dichloro-phenyl CH₃

H NMR (¹H, CDCl₃, 55° C.):δ 7.43(bs, 1H), 7.23(bs, 2H), 4.30(bm,1H),3.80(bm, 1H), 3.59(m, 5H), 3.40(bm, 3H), 3.35(s, 3H), 3.29(s, 3H),2.26(bs, 3H), 2.24(bm, 1H), 1.75(bm, 1H).MS (m/z): 423 [MH]⁺. 1-1-42,4-trifluoro-methylphenyl CH₃

H NMR (¹H, CDCl₃): δ 7.99(s, 1H), 7.83(d, 1H), 7.48(d, 1H),4.06-3.24(bm, 5H),2.23-2.2(bm, 4H), 1.74-1.1(bm, 10H),0.97(t, 3H),0.91(t, 3H).MS (m/z): 487[MH]⁺. 1-1-5 2,4-dichloro-phenyl CH₃

H NMR (¹H, CDCl₃): δ 7.46(d, 1H), 7.29(d, 1H), 7.26(dd, 1H), 4.04(m,1H), 3.67(t, 1H), 3.64(bm, 2H), 3.41(m, 1H), 3.20(t, 1H), 2.27(m, 4H),1.55-1.10(m, 8H),0.95(t, 3H), 0.88(t, 3H).MS (m/z): 419 [MH]⁺ 2Cl.

Example 2 Synthesis of Representative Compounds of Structure (1-2)9-(2,4-Dichlorophenyl)-4-(1-ethylpropyl)-2-methyl-5,6,6a,7,8,9-hexahydro-4H-1,3,4-triazaphenalene(isomer 1) and9-(2,4-Dichlorophenyl)-4-(1-ethylpropyl)-2-methyl-5,6,6a,7,8,9-hexahydro-4H-1,3,4-triazaphenale(isomer 2) (2-1-1)

Intermediate 25 (isomer 1) was dissolved in anh. CH₂Cl₂ (6 mL) andtreated with O₃ (5 g/hr) at −78° C. for 20 min. Dimethylsulfide (1 mL)was added and the mixture was allowed to warm to r.t. and stirredovernight. Then the reaction mixture was dried over Na₂SO₄, the solidswere filtered and the solvent evaporated. The crude aldehyde (106 mg)was obtained as a 1:1 mixture of two diastereoisomers and used withoutfurther purification. To a solution of the aldehyde prepared above (30mg) in anh. MeOH (1 mL), 1-ethyl-propylamine (0.010 mL) was added andthe reaction mixture was stirred at r.t. for 3 hr. A 1M solution ofNaBH₃CN in 1M (0.162 mL) was then added and the mixture was stirred atr.t. for 65 hr. Another aliquot of 1M NaBH₃CN in THF (0.080 mL) wasadded and the reaction was stirred at r.t. for 3 hr. The solvent wasevaporated and the residue was partitioned between water and EtOAc. Theaqueous layer was extracted with EtOAc (4×10 mL) and the combinedorganic extracts were washed with brine (2×10 mL), dried over anh.Na₂SO₄. The solids were filtered and the solvent evaporated. The crudeproduct was purified by flash chromatography (silica gel, CH₂Cl₂/EtOAc7:3) to give the title compound (16 mg) as a mixture of twodiastereoisomers.

The two diastereoisomers were separated by preparative TLC (1% NH₄OH intoluene/EtOAc 95:5) to give isomer 1 (5.4 mg) and isomer 2 (5.6 mg) asyellow oils.

All the analytical data are set forth in the following Table 2.

TABLE 2 (I-2)

Cpd. No. R R₁ R₂— R₃— Analytical Data 2-1-1 2,4-dichloro-phenyl CH₃

H Isomer 1: NMR (¹H, CDCl₃):δ 7.31(d, 1H), 7.14(dd, 1H), 7.01(bs,1H),5.01(bs, 1H), 4.41(bs, 1H), 3.34(bd, 1H), 3.17(dt, 1H), 2.68(m,1H),2.40-2.30(m, 1H), 2.37(bs, 3H), 2.04(m,2H), 1.67(bd, 1H), 1.55(m,4H), 1.50-1.35(m, 2H), 0.87(t, 3H), 0.79(t, 3H).MS (m/z): 404 [M+H].2,4-dichloro-phenyl CH₃

H Isomer 2: NMR (¹H, CDCl₃):δ 7.40(bs, 1H), 7.05(dd, 1H), 6.36(d,1H),5.03(bs, 1H), 5.00-4.50(broad, 1H),3.40(bd, 1H), 3.22(dt, 1H), 2.60(m,1H),2.45(bs, 3H), 2.16-2.06(m, 2H), 2.03(m,1H), 1.75(bd, 1H),1.70-1.50(m, 4H),1.45(dq, 1H), 1.24(m, 1H), 0.86(t, 6H).MS (m/z): 404[M+H]⁺.

Example 3 Synthesis of Representative Compounds of Structure (1-3)5-Cyclopropylmethyl-1-(2,4-dichlorophenyl)-7-methyl-1,2,2a,3,4,5-hexahydro-1,5,6,8-tetraaza-acenaphthylene(3-1-1)

To a solution of intermediate 10 (20 mg) in anh. CH₃OH (1 mL) was added(aminomethyl)cyclopropane (5 μl, 1 eq). The reaction was stirred at r.t.for 90 min and then NaBH₃CN 1.0M/THF (113 μl) was added. The mixture wasstirred for an additional 18 hr at r.t. and quenched with H₂O (10 mL).The product was extracted with EtOAc (2×15 mL), the combined extractswere dried over anh. Na₂SO₄, filtered and concentrated to dryness invacuo. Flash chromatography of the crude product (silica gel, cHex/EtOAc9:1) gave the title compound (5 mg) as a colourless oil.

1-(2,4-Dichlorophenyl)-5-(2-methoxyethyl)-7-methyl-1,2,2a,3,4,5-hexahydro-1,5,6,8-tetraaza-acenaphthylene(3-1-2)

To a solution of intermediate 10 (16 mg) in anh. THF (1 mL) was added2-methoxy-ethylamine (4 μl). The reaction was stirred at r.t. for 90 minand then NaBH₃CN 1.0M/THF (90 μl) was added. The mixture was stirred foran additional 18 hr at r.t. and quenched with H₂O (10 mL). The productwas extracted with EtOAc (2×15 mL). The combined extracts were driedover anh. Na₂SO₄, filtered and concentrated to dryness in vacuo. Thecrude product was dissolved in anh. THF (2 mL) and TEA (30 μl) wasadded. The reaction mixture was heated to reflux for 10 hr and quenchedwith H₂O. The product was extracted with EtOAc (2×10 mL). The combinedextracts were dried over anh. Na₂SO₄, filtered and concentrated todryness in vacuo. 2 mg (12%) of the title compound were obtained as alight beige oil after prep-TLC purification (eluted 3 times: 1: cHex100%, 2: cHex/EtOAc 75:25, 3: cHex/EtOAc 50:50).

1-(2,4-Dichlorophenyl)-5-(1-ethylpropol)-7-methyl-1,2,2a,3,4,5-hexahydro-1,5,6,8-tetraaza-acenaphthylene(3-1-3)

To a solution of intermediate 10 (20 mg) in anh. THF (1 mL) was added1-ethyl-propylamine (6.5 μl). The reaction mixture was stirred at r.t.for 90 min and then NaBH₃CN 1.0M/THF (112 μl) was added. The mixture wasstirred for an additional 18 hr at r.t. and quenched with water (10 mL).The product was extracted with EtOAc (2×10 mL). The combined extractswere dried over anh. Na₂SO₄, filtered and concentrated to dryness invacuo. The crude product was dissolved in anh. toluene (2 mL) and heatedto reflux for 18 hr. The reaction mixture was diluted with H₂O (10 mL)and extracted with EtOAc (3×10 mL). The combined organic extracts weredried over anh. Na₂SO₄, filtered and concentrated to dryness in vacuo togive the title compound (1.6 mg, 7%).) as a colourless oil afterprep-TLC purification (cHex/EtOAc 75:25).

1-(2,4-Dichlorophenyl)-5-(2-ethylbutyl)-7-methyl-1,2,2a,3,4,5-hexahydro-1,5,6,8-tetraaza-acenaphthylene(3-1-4)

To a solution of intermediate 10 (35.5 mg) in anh. MeOH (2 mL) was added2-ethylbutylamine (0.014 mL) at r.t., under N₂. The reaction mixture wasstirred at r.t. for 90 min. NaBH₃CN (1 N solution in THF, 0.2 mL) wasthen added at r.t. and the reaction mixture was heated to 70° C. for 3hr. It was then allowed to cool to r.t. and H₂O (5 mL) was added. Theorganic solvent was evaporated under reduced pressure and the aqueoussuspension was extracted with EtOAc (3×5 mL). The combined organiclayers were washed with sat. aq. NaCl (5 mL) and dried over anh. Na₂SO₄.The solids were filtered and the solvent evaporated. The crude productwas purified by flash chromatography (silica gel, cHex 100%→cHex/EtOAc95:5) to yield the title compound as a yellow solid (0.018 g).

1-(2,4-Dichlorophenyl)-7-methyl-5-(1-propylbutyl)-1,2,2a,3,4,5-hexahydro-1,5,6,8-tetraaza-acenaphthylene(3-1-5)

A solution intermediate 30 (20 mg, 0.046 mmol) in 4-aminoheptane (100μL) was heated at 130° C. (screw cap vial) for 6.5 hr, and then at r.t.for 18 hr. The amine was evaporated and the residue was directlypurified by flash chromatography (silica gel, cHex/EtOAc, 9:1) to givethe title compound as a clear oil (9 mg, 0.021 mmol, 47%).

7-Methyl-5-(1-propylbutyl)-1-(2,4-bis-trifluoromethyl-phenyl)-1,2,2a,3,4,5-hexahydro-1,5,6,8-tetraazaacenaphthylene(3-1-6)

Intermediate 37 (230 mg, 0.457 mmol) and 4-aminoheptane (0.68 mL, 10 eq)were heated at 130° C. (screw cap vial) for 14 hr. The reaction mixturewas diluted with CH₂Cl₂ and the solvent were evaporated. The crudeproduct was purified by flash chromatography (silica gel, cHex/EtOAc95:5) to give the title compound (54 mg, 0.11 mmol, 24%) as a whitesolid.

5-Cyclopropylmethyl-1-(2,4-dichlorophenyl)-7-methyl-4-propyl-1,2,2a,3,4,5-hexahydro-1,5,6,8-tetraazaacenaphthylene(3-1-7)

To a suspension of CuBr.Me₂S (48 mg, 5 eq) in anh. Et₂O (0.8 mL) at −50°C., under N₂, was added PrMgBr 1M/THF (0.188 mL, 4 eq) dropwise undervigorous stirring. The dark yellow mixture was stirred for 45 min at−50° C. and was then cooled to −78° C. BF₃.Et₂O (0.024 mL, 4 eq) wasadded and the reaction mixture was stirred for 20 min at −78° C. Asolution of intermediate 28 (19 mg, 0.047 mmol) in anh. THF (0.5 mL) wasadded and the reaction temperature was allowed to rise to r.t. over 3hr. After a total reaction time of 4 hr, a 1:1 mixture of conc. NH₄OHand sat.aq. NH₄Cl (2 mL) was added and the mixture was stirred for 15min. Water and EtOAc were added, the phases were separated and theaqueous layer was extracted with EtOAc (3×10 mL). The combined organicextracts were washed with water and dried over anh. Na₂SO₄. The solidswere filtered and the solvent evaporated. The crude product was purifiedby flash chromatography (silica gel, cHex/EtOAc 9:1). The title compoundwas obtained as a light yellow oil (3 mg, 0.007 mmol, 15%).

4-Butyl-5-cyclopropylmethyl-1-(2,4-dichlorophenyl)-7-methyl-1,2,2a,3,4,5-hexahydro-1,5,6,8-tetraazaacenaphthylene(3-1-8)

To a suspension of CuBr.Me₂S (72 mg, 4.3 eq) in anh. Et₂O (1 mL) at −50°C., under N₂, was added dropwise n-BuLi 1.6M/hexanes (0.21 mL, 4.15 eq)under vigorous stirring. The dark brown mixture was stirred for 40 minat −50° C., was then cooled at −78° C. and BF₃.Et₂O (0.043 mL, 4.15 eq)was added. After stirring for 15 minutes at −78° C., a solution ofintermediate 28 (33 mg, 0.081 mmol) in anh. THF (0.5 mL) was added andthe reaction temperature was allowed to rise to r.t. over 3 hr. After atotal reaction time of 3.5 hr, a 1:1 mixture of conc. NH₄OH and asat.aq. NH₄Cl (1 mL) was added and the mixture was stirred for 15 min.Water and EtOAc were then added, the phases were separated and theaqueous layer was extracted with EtOAc (3×10 mL). The combined organicextracts were washed with water and dried over anh. Na₂SO₄. The solidswere filtered and the solvent evaporated. The crude product was purifiedby flash chromatography (silica gel, cHex/EtOAc 9:1). The title compound(isomer 1: syn) was obtained as a pale yellow oil (16 mg, 0.037 mmol,46%). A small percentage of the anti isomer 2 was also isolated.

5-Cyclopropylmethyl-1-(2,4-dichlorophenyl)-7-methyl-4-propoxy-1,2,2a,3,4,5-hexahydro-1,5,6,8-tetraazaacenaphthylene(3-1-9)

To a suspension of CuBr.SMe₂ (27 mg, 2 eq) in anh. Et₂O (0.2 mL), at−60° C., under N₂, was added a solution of propyl magnesium bromide (0.2mL, 2 eq: prepared by the addition of Mg (27 mg, 1.1 mmol) and propylbromide in anh. Et₂O (1.5 mL), at r.t., under N₂, for 1 hr). The yellowheterogeneous reaction mixture was diluted with an additional 0.2 mL ofanh. Et₂O and stirred at −60° C. for 30 min. It was then cooled down to−78° C. and BF₃.Et₂O (17 μL, 2 eq) was added. After 10 min at −78° C., asolution of intermediate 28 (27 mg, 0.067 mmol) in anh. THF (0.4 mL) wasadded and the reaction mixture was slowly warmed to r.t. (4 hr). It wasthen diluted with a 1:1 mixture of conc. NH₄OH/sat.aq. NH₄Cl and stirredat r.t. for 10 min. The aqueous phase was then extracted with CH₂Cl₂(4×20 mL) and the combined organic extracts were washed with H₂O (2×20mL) and dried over anh. Na₂SO₄. The solids were filtered and the solventevaporated. The crude compound was purified by flash chromatography(silica gel, 9:1→7:3 cHex/EtOAc). The title compound was obtained as aclear oil (4 mg, 0.009 mmol, 14%)

4,5-Dibutyl-1-(2,4-dichlorophenyl)-7-methyl-1,2,2a,3,4,5-hexahydro-1,5,6,8-tetraazaacena-phthylene (3-1-10)

To a suspension of CuBr.Me₂S (65 mg, 4.3 eq) in anh. Et₂O (1 mL) cooledto −50° C., under N₂, a 1.6 M solution of BuLi (0.184 mL, 0.295 mmol, 4eq) was added dropwise under vigorous stirring. The dark brown mixturewas stirred for 40 min between −50° C. and −40° C., then it was cooledto −78° C. and BF₃.Et₂O (0.037 mL, 4 eq) was added. After stirring for15 min at −78° C., intermediate 28 was added (30 mg, 0.074 mmol)dissolved in anh. THF (0.5 mL) and the reaction temperature was allowedto rise to r.t. over 3 hr. After a total reaction time of 3.5 hr, a 1:1mixture of NH₄OH and a saturated solution of NH₄Cl (1 mL) was added andthe mixture was stirred for 15 min. Then water and EtOAc were added, thephases were separated and the aqueous layer was extracted with EtOAc(3×10 mL). The combined organic extracts were washed with water anddried over anh. Na₂SO₄. The solids were filtered and the solventevaporated. The crude product (28 mg) was purified by flashchromatography (cHex/EtOAc 9:1). The title compound (12 mg, 0.028 mmol,37%) was obtained as a colourless oil.

All the analytical data are set forth in the following Table 3.

TABLE 3 (I-3)

Cpd. No. R R₁ R₂— R₃— Analytical Data 3-1-1 2,4-dichloro-phenyl CH₃

H NMR (¹H, CDCl₃):δ 7.41(d, 1H), 7.36(d, 1H), 7.22(dd, 1H), 4.23(t, 1H),3.7(dd, 1H),3.55(t, 1H), 3.54-3.44(m, 3H),3.25(dd, 1H), 2.37(s, 3H),2.24(m, 1H), 1.66(m, 1H), 1.00(m,1H), 0.52(m, 2H), 0.29(m, 1H).MS (m/z):375 [MH]⁺, 2Cl. 3-1-2 2,4-dichloro-phenyl CH₃

H NMR (¹H, CDCl₃):δ 7.41(d, 1H), 7.35(d, 1H), 7.22(dd, 1H), 4.23(t, 1H),3.94(m,1H), 3.62-3.47(m, 5H), 3.37(s,3H), 2.38(s, 3H), 2.21(m,1H),1.64(m, 1H).MS (m/z) 379 [MH]⁺, 2Cl. 3-1-3 2,4-dicloro-phenyl CH₃

H NMR (¹H, CDCl₃):δ 7.41(d, 1H), 7.35(d, 1H), 7.22(dd, 1H), 4.23(t, 1H),3.94(m,1H), 3.62-3.47(m, 5H), 3.37(s,3H), 2.38(s, 3H), 2.21(m,1H),1.64(m, 1H).MS (m/z): 379 [MH]⁺, 2Cl. 3-1-4 2,4-dichloro-phenyl CH₃

H NMR (¹H, CDCl₃):δ 7.56-7.30(m, 3H), 4.25(t, 1H),3.68-3.40(m, 3H),2.56(s, 3H),2.45-2.27(m, 2H), 1.67(m, 6H),0.95(m, 8H).MS (m/z): 405[MH]⁺. 3-1-5 2,4-dichloro-phenyl CH₃

H NMR (¹H, CDCl₃): δ 7.35(m, 2H),7.20(d, 1H), 4.80(m, 1H), 4.20(t,1H),3.55(m, 1H), 3.45(m, 1H),3.35(m, 1H), 3.10(m, 1H), 2.30(s,3H), 2.20(m,1H), 1.60-1.15(m,9H), 0.90(m, 6H).MS (m/z): 419 [MH]⁺. 3-1-62,4-trifluoro-methylphenyl CH₃

H NMR (¹H, CDCl₃): δ 7.93(s, 1H),7.73(d, 1H), 7.59(d, 1H), 4.84(m,1H),4.14(t, 1H), 3.52(m, 1H),3.47(m, 1H), 3.37(m, 1H), 3.12(m, 1H), 2.34(s,3H), 2.27(m, 1H),1.6-1.2(m, 9H), 0.92(m, 6H).MS (m/z): 487 [MH]⁺. 3-1-72,4-dichloro-phenyl CH₃

NMR (¹H, CDCl₃):δ 7.40(d, 1H), 7.35(d, 1H), 7.20(dd, 1H), 4.27-4.10(m,2H), 3.68(m, 1H), 3.55-3.42(m, 2H), 3.03(dd, 1H), 2.35(s, 3H),2.40-2.25(m, 1H), 1.85-1.75(m, 1H), 1.75-1.50(m, 2H), 1.45-1.25(m,2H),0.95(t, 3H), 0.85(m, 1H), 0.55-0.25(m, 4H).MS (m/z): 417 [MH]⁺ 2Cl.3-1-8 2,4-dichloro-phenyl CH₃

Isomer 1 (syn):NMR (¹H, CDCl₃):δ 7.42(d, 1H), 7.37(d, 1H), 7.24(dd, 1H),4.24(m, 1H), 4.18(dd,1H), 3.72(m, 1H), 3.53(m, 1H),3.49(m, 1H), 3.06(dd,1H), 2.38(s, 3H), 2.32(m, 1H), 1.84(m, 1H),1.74(m, 1H), 1.62(q, 1h),1.45-1.25(m, 4H), 1.02(m, 1H), 0.94(t, 3H), 0.52(m, 1H), 0.44(m, 1H),0.38(m, 1H), 0.30(m, 1H).MS (m/z): 431 [M+H]⁺ (2 Cl).2,4-dichloro-phenyl CH₃

Isomer 2 (anti):NMR (¹H, CDCl₃):δ 7.43(d1H), 7.39(d, 1H), 7.23(dd, 1H),4.27(m, 1H), 4.08(dd,1H), 3.69(m, 1H), 3.57(m, 1H),3.49(m, 1H), 2.99(dd,1H), 2.39(s, 3H), 2.24(m, 1H), 1.80-1.20 (m,7H), 1.02(m, 1H), 0.94(t,3H),0.55(m, 1H), 0.46(m, 1H), 0.29(m, 2H).MS (m/z): 431 [M+H]⁺ 2Cl.3-1-9 2,4-dichloro-phenyl CH₃

NMR (¹H, Acetone-d₆): δ 7.55(d,1H), 7.48(d, 1H), 7.37(d, 1H),5.03(t,1H), 4.25(t, 1H), 4.03(dd,1H), 3.78(dd, 1H), 3.56(m, 3H),3.15(dd, 1H),2.54(m, 1H), 2.25(s, 3H), 1.59(m, 2H), 1.43(td, 1H),1.11(m, 1H), 0.92(t,3H), 0.50-0.24(m, 4H).MS (m/z): 433 [MH]⁺. 3-1-10 2,4-dichloro-phenylCH₃

NMR (¹H, CDCl₃): δ 7.54(d, 1H),7.47(d, 1H), 7.36(dd, 1H), 4.39(m, 1H),4.19(m, 1H), 3.68(m,1H), 3.59(m, 1H), 3.50(m, 1H),3.07(m, 1H), 2.40(m,1H), 2.20(s,3H), 1.90-1.70(m, 3H), 1.60-1.50(m, 3H), 1.40-1.20(m, 5H),0.95(2t, 6H).MS (m/z): 433 [M+H]⁺ (2 Cl).

Example 4 Synthesis of Representative Compounds of Structure (1-4)5-(2,4-Dichlorophenyl-1-(1-ethylpropyl)-7-methyl-1,2,2a,3,4,5-hexahydro-1,6,8-triaza-acenaphthylene (4-1-1)

To a solution of intermediate 47 (22 mg, 0.062 mmol) in anh. MeOH (1mL), under N₂, at r.t., was added 1-ethyl propylamine (9 μL, 1.25 eq)and the reaction mixture was stirred at r.t. for 1.25 hr. NaBH₃CN1.0M/THF (0.15 mL, 2.4 eq) was then added and the reaction mixture wasstirred at r.t. for 2 hr, then at −18° C. for 4 days. The solvent wasevaporated and the residue partitioned between EtOAc/H₂O. The phaseswere separated and the aqueous layer was extracted with EtOAc (3×5 mL).The combined organic extracts were washed with sat.aq. NaCl (1×5 mL) anddried over anh. Na₂SO₄. The solids were filtered and the solventevaporated. The crude product was purified by flash chromatography(silica gel, cHex/EtOAc 9:1→8:2). The title compound was obtained as aclear oil (3 mg, 0.008 mmol, 12%).

All the analytical data are set forth in the following Table 4.

TABLE 4 (I-4)

Cpd. No. R R₁ R₂— R₃— Analytical Data 4-1-1 2,4-dichloro-phenyl CH₃

H MS (m/z): 390 [MH]⁺ (2 Cl).

Example 5 CRF Binding Activity

CRF binding affinity has been determined in vitro by the compounds'ability to displace ¹²⁵I-oCRF and ¹²⁵I-Sauvagine for CRF1 and CRF2 SPA,respectively, from recombinant human CRF receptors expressed in ChineseHamster Ovary (CHO) cell membranes. For membrane preparation, CHO cellsfrom confluent T-flasks were collected in SPA buffer (HEPES/KOH 50 mM,EDTA 2 mM; MgCl₂ 10 mM, pH 7.4.) in 50 mL centrifuge tubes, homogenizedwith a Polytron and centrifuged (50,000 g for 5 min at 4° C.: Beckmancentrifuge with JA20 rotor). The pellet was resuspended, homogenized andcentrifuged as before.

The SPA experiment has been carried out in Optiplate by the addition of100 μL the reagent mixture to 1 μL of compound dilution (100% DMSOsolution) per well. The assay mixture was prepared by mixing SPA buffer,WGA SPA beads (2.5 mg/mL), BSA (1 mg/mL) and membranes (50 and 5 μg ofprotein/mL for CRF1 and CRF2 respectively) and 50 pM of radioligand.

The plate was incubated overnight (>18 hr) at room temperature and readwith the Packard Topcount with a WGA-SPA ¹²⁵I counting protocol.

Example 6 CRF Functional Assay

Compounds of the invention were characterised in a functional assay forthe determination of their inhibitory effect. Human CRF-CHO cells werestimulated with CRF and the receptor activation was evaluated bymeasuring the accumulation of cAMP.

CHO cells from a confluent T-flask were resuspended with culture mediumwithout G418 and dispensed in a 96-well plate, 25'000 c/well, 100μL/well and incubated overnight. After the incubation the medium wasreplaced with 100 μL of cAMP IBMX buffer warmed at 37° C. (5 mM KCl, 5mM NaHCO₃, 154 mM NaCl, 5 mM HEPES, 2.3 mM CaCl₂, 1 mM MgCl₂; 1 g/Lglucose, pH 7.4 additioned by 1 mg/mL BSA and 1 mM IBMX) and 1 μL ofantagonist dilution in neat DMSO. After 10 additional minutes ofincubation at 37° C. in a plate incubator without CO2, 1 μL of agonistdilution in neat DMSO was added. As before, the plate was incubated for10 minutes and then cAMP cellular content was measured by using theAmersham RPA 538 kit.

All publications, including but not limited to patents and patentapplications, cited in this specification are herein incorporated byreference as if each individual publication were specifically andindividually indicated to be incorporated by reference herein as thoughfully set forth.

It is to be understood that the present invention covers allcombinations of particular and preferred groups described herein above.

The application of which this description and claims forms part may beused as a basis for priority in respect of any subsequent application.The claims of such subsequent application may be directed to any featureor combination of features described herein. They may take the form ofproduct, composition, process, or use claims and may include, by way ofexample and without limitation, the following claims:

1. A compound of formula (I), or a pharmaceutically acceptable saltthereof:

wherein R is aryl or heteroaryl, wherein each of the above groups R maybe substituted by 1 to 4 substituents independently selected from thegroup consisting of: halogen, C1-C6 alkyl, C1-C6 alkoxy, halo C1-C6alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo C1-C6 alkoxy, C1-C6 mono ordialkylamino, nitro, cyano and a group R₄; R₁ is hydrogen, C1-C6 alkyl,C2-C6 alkenyl, C2-C6 alkynyl, halo C1-C6 alkyl, halo C1-C6 alkoxy, NH₂,halogen or cyano; R₂ is hydrogen or C(H)_(n)(R₅)_(q)(CH₂)_(p)ZR₆; R₃ ishydrogen, C2-C6 alkenyl, C2-C6 alkynyl or [CH(R₅)(CH₂)_(p)]_(m)ZR₆; R₄is C3-C7 cycloalkyl, which may contain one or more double bonds; aryl;or a 5-6 membered heterocycle; wherein each of the above groups R₄ maybe substituted by one or more groups selected from: halogen, C1-C6alkyl, C1-C6 alkoxy, halo C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl,halo C1-C6 alkoxy, C1-C6 mono or dialkylamino, nitro, and cyano; R₅ ishydrogen, C2-C6 alkenyl, C2-C6 alkynyl or (CH₂)_(p)ZR₆; R₆ is C1-C6alkyl, which may be substituted by one or more groups selected fromhalogen, halo C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo C1-C6alkoxy, C1-C6 alkoxy, C1-C6 mono or dialkylamino, nitro, cyano and agroup R4; X is carbon; Y is carbon or nitrogen; m and n areindependently 0 or 1; p is 0 or an integer from 1 to 4; q is 1 or 2; andZ is a bond, O, NH or S.
 2. A compound, according to claim 1, of formula(IIa)

in which R, R₁, R₂, R₃, n and Y are defined as in claim 1 or apharmaceutically acceptable salt thereof.
 3. A compound, according toclaim 1, of formula (IIb)

in which R, R₁, R₂, R₃, n and Y are defined as in claim
 1. 4. Acompound, according to claim 1, of formula (IIc)

in which R, R₁, R₂, R₃, m and Y are defined as in claim 1 or apharmaceutically acceptable salt thereof.
 5. A compound, according toclaim 1, of formula (IId)

in which R, R₁, R₂, R₃, m and Y are defined as in claim 1 or apharmaceutically acceptable salt thereof.
 6. A compound, according toclaim 4, of formula (Ia-1)

in which R, R₁, R₂, R₃ and Y are defined as in claim 1 or apharmaceutically acceptable salt thereof.
 7. A compound, according toclaim 4, of formula (Ib-1)

in which R, R₁, R₂, R₃ and Y are defined as in claim 1 or aphannaceutically acceptable salt thereof.
 8. A compound, according toclaim 2, of formula (Ic-1)

in which R, R₁, R₂, R₃ and Y are defined as in claim 1 or apharmaceutically acceptable salt thereof.
 9. A compound, according toclaim 7, of formula (I-1),

in which R, R₁, R₂, R₃ are defined as in claim 1 or a pharmaceuticallyacceptable salt thereof.
 10. A compound, according to claim 6, offormula (I-2),

in which R, R₁, R₂, R₃ are defined as in claim 1 or a phannaceuticallyacceptable salt thereof.
 11. A compound, according to claim 5, offormula (I-3),

in which R, R₁, R₂, R₃ are defined as in claim 1 or a pharmaceuticallyacceptable salt thereof.
 12. A compound, according to claim 7, offormula (I-4),

in which R, R₁, R₂, R₃ are defined as in claim 1 or a pharmaceuticallyacceptable salt thereof.
 13. A compound, according to claim 1, whereinR₂ and R₃ are not simultaneously hydrogen; or a pharmaceuticallyacceptable salt thereof.
 14. A compound, according to claim 1, whereinR₁ is C1-C3 alkyl group or halo C1-C3 alkyl group; or a phannaccuticallyacceptable salt thereof.
 15. A compound, according to claim 1, wherein Ris an aryl group selected from: 2,4-dichlorophenyl,2-chloro-4-methylphenyl, 2-chloro-4-trifluoromethylphenyl,2-chloro-4-methoxyphenyl, 2,4,5-trimethyiphenyl, 2,4-dimethyl-phenyl,2-methyl-4-methoxyphenyl, 2-methyl-4-chlorophenyl,2-methyl-4-trifluoromethylphenyl, 2,4-dimethoxyphenyl,2-methoxy-4-trifluoromethylphenyl, 2-methoxy-4-chlorophenyl,3-methoxy-4-chlorophenyl, 2,5-dimethoxy-4-chlorophenyl,2-methoxy-4-isopropylphenyl, 2-methoxy-4-trifluoromethylphenyl,2-methoxy-4-isopropylphenyl 2-methoxy-4-methylphenyl,2-trifluoromethyl-4-chlorophenyl, 2,4-trifluoromethylphenyl,2-trifluoromethyl-4-methylphenyl, 2-trifluoromethyl-4-methoxyphenyl,2-bromo-4-isopropylphenyl, 4-methyl-6-dimethylaminopyridin-3-yl,4-dimethylamino-6-methyl-pyridin-3-yl, 6-dimethylamino-pyridin-3-yl and4-dimethylamino-pyridin-3-yl; or a pharmaceutically acceptable saltthereof.
 16. A compound, according to claim 1, selected from the groupconsisting of:5-(2,4-dichlorophenyl)-1-(1-ethylpropyl)-7-methyl-1,2,2a,3,4,5-hexahydro-1,5,6,8-tetraaza-acenaphthylene;5-(2,4-dichlorophenyl)-1-(2-ethylbutyl)-7-methyl-1,2,2a,3,4,5,5a,8b-octahydro-1,5,6,8-tetraazaacenaphthylene;5-(2,4-dichlorophenyl)-1-(2-methoxy-1-methoxymethylethyl)-7-methyl-1,2,2a,3,4,5,5a,8b-octahydro-1,5,6,8-tetraazaacenaphthylene;7-methyl-1-(1-propylbutyl)-5-[4-(1,1,2-trifluoroethyl)-2-trifluoromethylphenyl]-1,2,2a,3,4,5-hexahydro-1,5,6,8-tetraazaacenaphthylene;7-methyl-1-(1-propylbutyl)-5-[4-(1,1,2-trifluoroethyl)-2-trifluoromethylphenyl]-1,2,2a(S),3,4,5-hexahydro-1,5,6,8-tetraazaacenaphthylene;7-methyl-1-(1-propylbutyl)-5-[4-(1,1,2-trifluoroethyl)-2-trifluoromethylphenyl]-1,2,2a(R),3,4,5-hexahydro-1,5,6,8-tetraazaacenaphthylene;5-(2,4-dichlorophenyl)-7-methyl-1-(1-propylbutyl)-1,2,2a,3,4,5-hexahydro-1,5,6,8-tetraazaacenaphthylene;5-(2,4-dichlorophenyl)-7-methyl-1-(1-propylbutyl)-1,2,2a-(S),3,4,5,5a,8b-octahydro-1,5,6,8-tetraazaacenaphthylene;5-(2,4-dichlorophenyl)-7-methyl-1-(1-propylbutyl)-1,2,2a-(R),3,4,5,5a,8b-octahydro-1,5,6,8-tetraazaacenaphthylene;9-(2,4-dichlorophenyl)-4-(1-ethylpropyl)-2-methyl-5,6,6a,7,8,9-hexahydro-4H-1,3,4-triazaphenalene(isomer 1) and9-(2,4-dichlorophenyl)-4-(1-ethylpropyl)-2-methyl-5,6,6a,7,8,9-hexahydro-4H-1,3,4-triazaphenalene(isomer 2);5-cyclopropylmethyl-1-(2,4-dichlorophenyl)-7-methyl-1,2,2a,3,4,5-hexahydro-1,5,6,8-tetraazaacenaphthylene;1-(2,4-dichlorophenyl)-5-(2-methoxyethyl)-7-methyl-1,2,2a,3,4,5-hexahydro-1,5,6,8-tetraazaacenaphthylene;1-(2,4-dichlorophenyl)-5-(1-ethylpropyl)-7-methyl-1,2,2a,3,4,5-hexahydro-1,5,6,8-tetraazaacenaphthylene;1-(2,4-dichlorophenyl)-5-(2-ethylbutyl)-7-methyl-1,2,2a,3,4,5-hexahydro-1,5,6,8-tetraazaacenaphthylene;1-(2,4-dichlorophenyl)-7-methyl-5-(1-propylbutyl)-1,2,2a,3,4,5-hexahydro-1,5,6,8-tetraazaacenaphthylene;7-methyl-5-(1-propylbutyl)-1-[4-(1,1,2-trifluoro-ethyl)-2-trifluoromethylphenyl]-1,2,2a,3,4,5-hexahydro-1,5,6,8-tetraazaacenaphthylene;5-cyclopropylmethyl-1-(2,4-dichlorophenyl)-7-methyl-4-propyl-1,2,2a,3,4,5-hexahydro1,5,6,8-tetraazaacenaphthylene;4-butyl-5-cyclopropylmethyl-1-(2,4-dichlorophenyl)-7-methyl-1,2,2a,3,4,5-hexahydro1,5,6,8-tetraazaacenaphthylene;5-cyclopropylmethyl-1-(2,4-dichlorophenyl)-7-methyl-4-propoxy-1,2,2a,3,4,5-hexahydro1,5,6,8-tetraazaacenaphthylene;4,5-dibutyl-1-(2,4-dichlorophenyl)-7-methyl-1,2,2a,3,4,5-hexahydro-1,5,6,8-tetraaza-acenaplithylene; and5-(2,4-dichlorophenyl)-1-(1-ethylpropyl)-7-methyl-1,2,2a,3,4,5-hexahydro-1,6,8-triaza-acenaphthylene;or a pharmaceutically acceptable salt thereof.
 17. A pharmaceuticalcomposition comprising a compound according to claim 1, or apharmaceutically acceptable salt thereof, in admixture with one or morephysiologically acceptable carriers or excipients.